Peptide yy analogs

ABSTRACT

The invention provides analogs of PYY. The invention also provides compositions and methods useful for controlling biological activities such as cell proliferation, nutrient transport, lipolysis, and intestinal water and electrolyte secretion.

FIELD OF THE INVENTION

This invention relates to peptides which are useful as therapeuticagents in the treatment of feeding and gastroenterological conditionsand disorders.

BACKGROUND OF THE INVENTION

Peptide YY (PYY) is a 36-residue peptide amide isolated originally fromporcine intestine, and localized in the endocrine cells of thegastrointestinal tract and pancreas (Tatemoto et al. Proc. Natl. Acad.Sci. 79:2514, 1982). PYY shares a number of central and peripheralregulatory roles with its homologous peptide Neuropeptide Y (NPY), whichwas originally isolated from porcine brain (Tatemoto, Proc. Natl. Acad.Sci. 79:5485, 1982). PYY is localized in intestinal cells; NPY, incontrast, is present in the submucous and myenteric neurons whichinnervate the mucosal and smooth muscle layers, respectively (Ekblad etal. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibitgut motility and blood flow (Laburthe, Trends Endocrinol. Metab. 1:168,1990), and they are also thought to attenuate basal (Cox et al. Br. JPharmacol. 101:247, 1990; Cox et al. J. Physiol. 398:65, 1988; Cox etal. Peptides 12:323, 1991; Friel et al. Br. J. Pharmacol. 88:425, 1986)and secretagogue-induced intestinal secretion in rats (Lundberg et al.Proc. Natl. Acad. Sci USA 79:4471, 1982; Playford et al. Lancet335:1555, 1990) and humans (Playford et al., supra), as well asstimulate net absorption (MacFadyen et al. Neuropeptides 7:219, 1986).Elevated plasma PYY levels have been reported in individuals sufferingfrom several conditions that cause diarrhea (Adrian et al.Gastroenterology 89:1070, 1985). Taken together, these observationssuggest that PYY and NPY are released into the circulation after a meal(Adrian et al. Gastroenterology 89:1070, 1985; Balasubramaniam et al.Neuropeptides 14:209, 1989), and, thus, may play a physiological role inregulating intestinal secretion and absorption, serving as naturalinhibitors of diarrhea.

A high affinity PYY receptor system which exhibits a slightly higheraffinity for PYY than NPY has been characterized in rat intestinalepithelia (Laburthe et al. Endocrinology118:1910, 1986; Laburthe, TrendsEndocrinol. Metab. supra) and shown to be negatively coupled toadenylate cyclase (Servin et al. Endocrinology 124:692, 1989).Consistently, PYY exhibited greater antisecretory potency than NPY involtage clamped preparations of rat small intestine (Cox et al. J.Physiol. supra), while C-terminal fragments of NPY were found to be lesseffective in their antisecretory potency than PYY (Cox et al. Br. J.Pharmacol. supra). Structure-activity studies using several partialsequences have led to the identification of PYY(22-36) as the activesite for interacting with intestinal PYY receptors (Balsubramaniam etal. Pept. Res. 1:32, 1988). PYY[3-36] is reportedly a selective ligandat the Y2 and Y5 receptors, which appear pharmacologically unique inpreferring N-terminally truncated (i.e. C-terminal fragments of) NPYanalogs.

PYY has been implicated in a number of physiological activitiesincluding nutrient uptake (see, e.g., Bilcheik et al. Digestive DiseaseWeek 506:623, 1993), cell proliferation (see, e.g., Laburthe, TrendsEndocrinol. Metab. 1:168, 1990; Voisin et al. J. Biol. Chem, 1993),lipolysis (see, e.g., Valet et al., J. Clin. Invest. 85:291, 1990), andvasoconstriction (see, e.g., Lundberg et al., Proc. Natl. Acad. Sci.,USA 79:4471, 1982). Recently it has been suggested that infusion ofnormal postprandial concentrations of PYY(3-36) significantly reducesappetite and food intake in humans (see Batterham et al., Nature418:656-654, 2002; Batterham et al., N Engl J Med. 349:941, 2003).

Peripheral administration of PYY reportedly reduces gastric acidsecretion, gastric motility, exocrine pancreatic secretion (Yoshinaga,Mochizuki et al. Am J Physiol 263: G695-701, 1992) (Guan, Maouyo et al.Endocrinology 128: 911-6, 1991) (Pappas, Debas et al. Gastroenterology91: 1386-9, 1986), gallbladder contraction and intestinal motility(Savage, Adrian et al. Gut 28: 166-70, 1987). The effects of centralinjection of PYY on gastric emptying, gastric motility and gastric acidsecretion, as seen after direct injection in or around thehindbrain/brainstem (Chen and Rogers. Am J Physiol 269: R787-R792, 1995)(Chen, Rogers et al. Regul Pept 61: 95-98, 1996) (Yang and Tache. Am JPhysiol 268: G943-8, 1995) (Chen, Stephens et al. NeurogastroenterolMotil 9: 109-116, 1997), may differ from those effects observed afterperipheral injection. For example, centrally administered PYY had someeffects opposite to those described herein for peripherally injectedPYY[3-36] in that gastric acid secretion was stimulated, not inhibited.Gastric motility was suppressed only in conjunction with TRHstimulation, but not when administered alone, and was indeed stimulatoryat higher doses through presumed interaction with PP receptors. PYY hasbeen shown to stimulate food and water intake after centraladministration (Morley, Levine et al. Brain Res 341: 200-203, 1985)(Corp, Melville et al. Am J Physiol 259: R317-23, 1990).

Pharmacological studies and cloning efforts have revealed a number ofseven transmembrane receptors for the PP family of peptides, and thesereceptors have been assigned the names Y1 through Y6 (and a putativePYY-preferring receptor or Y7). Typical signaling responses of thesereceptors are similar to those of other G_(i)/G₀-coupled receptors,namely inhibition of adenylate cyclase. It is apparent that there is aclustering of amino acid sequence similarity between Y1, Y4 and Y6receptors, while Y2 and Y5 define other families. Other binding siteshave been identified by the rank order of potency of various peptides.The NPY-preferring receptor has been termed Y3, and PYY-preferringreceptors have also been shown to exist (putative Y7) (See Michel,Beck-Sickinger et al. Pharmacol Rev 50:143-50, 1998; and Gehlert, D. R.Proc Soc Exp Biol Med 218: 7-22, 1998).

The Y5 and Y1 receptors have been suggested as the primary mediators ofthe food intake response (Marsh, Hollopeter et al. Nat Med 4: 718-21,1998) (Kanatani, A., Mashiko, S., Murai, N., Sugimoto, N., Ito, J.,Fukuroda, T., Fukami, T., Morin, N., MacNeil, D. J., Van der Ploeg, L.H., Saga, Y., Nishimura, S., and Ihara, M. Endocrinology 141: 1011-6,2000). The prevalent idea has been that endogenous NPY, via thesereceptors, increases feeding behavior. Some proposed therapies forobesity have been directed toward antagonism of NPY receptors, whiletherapies for treating anorexia have been directed toward agonists ofthis ligand family (see, e.g., U.S. Pat. Nos. 5,939,462; 6,013,622; and4,891,357). In general, PYY and NPY are reported to be equipotent andequally effective in all Y1, Y5 (and Y2) receptor assays studied(Gehlert, D. R. Proc Soc Exp Biol Med 218: 7-22, 1998). The maincharacteristic of putative Y3 receptors is that they recognize NPY,while PYY is at least an order of magnitude less potent. The Y3 receptorrepresents the only binding site/receptor shown to have a preference forNPY.

There is an additional binding site/receptor which shows preference forPYYs, termed PYY-preferring receptor. Different rank orders of bindingto this receptor, or class of receptors, have been reported, suggestingthat there may be more than one receptor in this family. In most casesit has been applied to describe a receptor where PYY was three to fivetimes more potent than NPY. For purposes of this disclosure, referenceto pharmacology of a PYY-preferring receptor means a receptor having anydegree of preference for PYY over NPY.

Obesity and its associated disorders are common and very serious publichealth problems in the United States and throughout the world. Upperbody obesity is the strongest risk factor known for type 2 diabetesmellitus, and is a strong risk factor for cardiovascular disease.Obesity is a recognized risk factor for hypertension, atherosclerosis,congestive heart failure, stroke, gallbladder disease, osteoarthritis,sleep apnea, reproductive disorders such as polycystic ovarian syndrome,cancers of the breast, prostate, and colon, and increased incidence ofcomplications of general anesthesia. (see, e.g., Kopelman, Nature 404:635-43, 2000). It reduces life-span and carries a serious risk ofco-morbidities above, as well disorders such as infections, varicoseveins, acanthosis nigricans, eczema, exercise intolerance, insulinresistance, hypertension, hypercholesterolemia, cholelithiasis,orthopedic injury, and thromboembolic disease (Rissanen, Heliovaara etal. BMJ 301: 8357, 1990). Obesity is also a risk factor for the group ofconditions called insulin resistance syndrome, or “Syndrome X.” Thepathogenesis of obesity is believed to be multifactorial but the basicproblem is that in obese subjects nutrient availability and energyexpenditure do not come into balance until there is excess adiposetissue. Obesity is currently a poorly treatable, chronic, essentiallyintractable metabolic disorder. Thus there remains a need fortherapeutic drugs useful in weight reduction of obese persons.

SUMMARY OF THE INVENTION

Peripheral administration of PYY and PYY agonists reduces nutrientavailability and is useful in the treatment of obesity and relateddisorders. PYY and PYY agonist compositions and uses thereof aredisclosed herein to modulate nutrient availability in a patient fortreating metabolic disorders which may be benefited by a reduction innutrient availability. These methods will be useful in the treatment of,for example, obesity, diabetes, including but not limited to type 2 ornon-insulin dependent diabetes, eating disorders, insulin-resistancesyndrome, and cardiovascular disease.

Unless otherwise indicated the term “PYY” refers to a Peptide YYpolypeptide obtained or derived from any species. Thus, the term “PYY”includes both the human full length, 36 amino acid peptide as set forthin SEQ ID NO: 1, and species variations of PYY, including e.g., murine,hamster, chicken, bovine, rat, and dog PYY. By “PYY agonist” is meantany compound which elicits one of more of the effects elicited by PYY invivo or in vitro. For example, a PYY agonist of the invention may reducenutrient availability, for example, by augmenting food intake, gastricemptying, pancreatic secretion, or weight loss, and bind in a PYYreceptor assay, or in a competitive binding assay with labeled PYY orPYY[3-36] from certain tissues having an abundance of Y receptors,including e.g., area postrema, wherein the PYY agonist is not pancreaticpolypeptide. Preferably, PYY agonists would bind in such assays with anaffinity of greater than about 1 μM, more preferably with an affinity ofgreater than about 10 nM, more preferably still with an affinity ofgreater than about 1 nM. Also preferably, analogs of the inventioncomprise compounds according to formula (I) that bind in such assayswith an affinity of greater than about 1 μM, more preferably with anaffinity of greater than about 10 nM, more preferably still with anaffinity of greater than about 1 nM.

By “condition or disorder which can be alleviated by reducing caloric(or nutrient) availability” is meant any condition or disorder in asubject that is either caused by, complicated by, or aggravated by arelatively high nutrient availability, or that can be alleviated byreducing nutrient availability, for example by decreasing food intake.Such conditions or disorders include, but are not limited to, obesity,diabetes, including type-2 diabetes, eating disorders, andinsulin-resistance syndromes.

In one aspect, the invention provides a method of treating obesity in anobese or overweight subject by administering a therapeutically effectiveamount of a PYY agonist of the invention. While “obesity” is generallydefined as a body mass index over 30, for purposes of this disclosure,any subject, including those with a body mass index of less than 30, whoneeds or wishes to reduce body weight is included in the scope of“obese.” Subjects who are insulin resistant, glucose intolerant, or haveany form of diabetes mellitus (e.g., type 1, 2 or gestational diabetes)can benefit from this method.

In other aspects, the invention features methods of reducing foodintake, treating diabetes mellitus, and improving lipid profile(including reducing LDL cholesterol and triglyceride levels and/orchanging HDL cholesterol levels) comprising administering to a subject atherapeutically effective amount of a compound according to formula (I).In a preferred embodiment, a method of the invention is used to treat acondition or disorder which can be alleviated by reducing nutrientavailability in a subject in need thereof, comprising administering tosaid subject a therapeutically effective amount of a PYY agonist of theinvention. Such conditions and disorders include, but are not limitedto, hypertension, dyslipidemia, cardiovascular disease, eatingdisorders, insulin-resistance, obesity, and diabetes mellitus of anykind.

The amino acid sequences for human and for rat PYY are as follows

human: YPIKP EAPGE DASPE ELNRY YASLR HYLNL VTRQR Y (SEQ ID NO:1)

rat: YPAKP EAPGE DASPE ELSRY YASLR HYLNL VTRQR Y (SEQ ID NO:2)

Further PYY amino acid sequences are well known, including, e.g.,porcine, hamster, canine, bovine, and avian (e.g, chicken).

The following patents and patent publications, the disclosure of each ofwhich is incorporated herein by reference in its entirety, disclosecertain PYY analogs and uses thereof: EP0692971, EP0732875, EP0746332,EP0802972, EP1007073, EP1015007, US2002/103123, US2002/141985, U.S. Pat.No. 5,516,653, U.S. Pat. No. 5,545,549, U.S. Pat. No. 5,574,010, U.S.Pat. No. 5,602,024, U.S. Pat. No. 5,604,203, U.S. Pat. No. 5,912,227,U.S. Pat. No. 5,916,869, U.S. Pat. No. 5,968,819, U.S. Pat. No.5,976,814, U.S. Pat. No. 5,989,834, U.S. Pat. No. 5,989,920, U.S. Pat.No. 6,046,167, U.S. Pat. No. 6,087,154, U.S. Pat. No. 6,242,251, U.S.Pat. No. 6,316,203, U.S. Pat. No. 6,355,478, WO01/54486, WO02/47712,WO93/24515, WO94/22467, WO95/17906, WO95/21245, WO96/14854, WO96/16542,WO96/22783, WO97/46250, WO97/48406, and WO98/20885.

Notwithstanding the foregoing there remains a continuing need for PYYanalogs having improved PYY potency and/or selectivity and/or in vitroor in vivo characteristics.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to the peptides formula(I):(R²,R³)A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-R¹  (I)

wherein:

A³ is Acc, Act, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Ile, Leu, Nle, Tle, hLeu, Cha, Val, Ala,Nva, and Abu, or the N-methylated variant of Acc, Act, or Aib, or ofsaid D- or L-amino acid, or is deleted;

A⁴ is Aib, Acc, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Lys, Arg, hArg, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylated variant of Aib, Acc,or Apc, or of said D- or L-amino acid, or is deleted;

A⁵ is Inc, or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, orthe N-methylated variant of Inc or of said D- or L-amino acid, or isdeleted;

A⁶ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Glu, Asp, Gln, Asn, Lys, Arg, Orn, Dab, Dap,and hArg, or the N-methylated variant of Acc or Aib, or of said D- orL-amino acid, or is deleted;

A⁷ is Acc, Act, Aib, Apc, or Gly, or a D- or L-amino acid selected fromthe list of amino acids consisting of Ala, Abu, Val, and Nva, or theN-methylated variant of Acc, Act, Aib, Apc, or Gly, or of said D- orL-amino acid, or is deleted;

A⁸ is Inc or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, orthe N-methylated variant of Inc or of said D- or L-amino acid, or isdeleted;

A⁹ is Acc, Aib, or Gly, or D- or L-Ala, or the N-methylated variant ofAcc, Aib, Gly, or D- or L-Ala, or is deleted;

A¹⁰ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Glu, Asp, Gln, and Asn, or the N-methylatedvariant of Acc or Aib, or of said D- or L-amino acid, or is deleted;

A¹¹ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Asp, Glu, Gln, and Asn, or the N-methylatedvariant of Acc or Aib, or of said D- or L-amino acid, or is deleted;

A¹² is Acc, Act, Aib, Apc, or Gly, or a D- or L-amino acid selected fromthe list of amino acids consisting of Ala, Abu, Val, and Nva, or theN-methylated variant of Acc, Act, Aib, Apc, or Gly, or of said D- orL-amino acid, or is deleted;

A¹³ is Acc, Aib, or Act, or a D- or L-amino acid selected from the listof amino acids consisting of Ser, Thr, Ala, Abu, and Val, or theN-methylated variant of Acc, Aib, or Act, or of said D- or L-amino acid,or is deleted;

A¹⁴ is Inc or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, orthe N-methylated variant of Inc or of said D- or L-amino acid, or isdeleted;

A¹⁵ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Glu, Asp, Gln, and Asn, or the N-methylatedvariant of Acc or Aib, or of said D- or L-amino acid, or is deleted;

A¹⁶ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Glu, Asp, Gln, and Asn, or the N-methylatedvariant of Acc or Aib, or of said D- or L-amino acid, or is deleted;

A¹⁷ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva,Abu, and Phe, or the N-methylated variant of Acc or Aib, or of said D-or L-amino acid, or is deleted;

A¹⁸is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Asn, Gln, Glu, and Asp, or the N-methylatedvariant of Acc or Aib, or of said D- or L-amino acid, or is deleted;

A¹⁹ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylated variant of Acc, Aib,or Apc, or of said D- or L-amino acid, or is deleted;

A²⁰ is Acc or Aic, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X^(1,)X²,X³ X⁴,X⁵)Phe, or theN-methylated variant of Acc or Aic, or of said D- or L-amino acid, or isdeleted;

A²¹ is Acc or Aic, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or theN-methylated variant of Acc or Aic, or of said D- or L-amino acid, or isdeleted;

A²² is Acc, Act, Aib, Apc, or Gly, or a D- or L-amino acid selected fromthe list of amino acids consisting of Ala, Aib, Abu, Val, and Nva, orthe N-methylated variant of Acc, Act, Aib, Apc, or Gly, or of said D- orL-amino acid, or is deleted;

A²³ is Acc, Act, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Ser, Thr, Ala, Abu, and Val, or theN-methylated variant of Acc, Act, or Aib, or of said D- or L-amino add,or is deleted;

A²⁴ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva,Abu, Trp, and Phe, or the N-methylated variant of Acc or Aib, or of saidD- or L-amino acid, or is deleted;

A²⁵ is Acc, Aib, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, Aib, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylated variant of Acc, Aib,or Aib, or of said D- or L-amino acid, or is deleted;

A²⁶ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of His, 2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi,2Fua, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), and (X¹,X²,X³,X⁴,X⁵-)Phe, or theN-methylated variant of Acc, Aib, or Apc, or of said D- or L-amino acid,or is deleted;

A²⁷ is Acc or Aic, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or theN-methylated variant of Acc or Aic or of said D- or L-amino acid;

A²⁸ is Acc or Aib, a D- or L-amino acid selected from the list of aminoacids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva,Abu, and Phe, or the N-methylated variant of Acc or Aib, or of said D-or L-amino acid;

A²⁹ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Asn, Gln, Glu, Asp, and Trp, or theN-methylated variant of Acc or Aib, or of said D- or L-amino acid;

A³⁰ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala,Nva, Abu, and Phe or the N-methylated variant of Acc or Aib, or of saidD- or L-amino acid;

A³¹ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Val, Leu, Ile, Nle, Tle, hLeu, Cha, Ala, Nva,Abu, Trp, and Phe, or the N-methylated variant of Acc or Aib, or of saidD- or L-amino acid;

A³² is Acc, Act, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Thr, Ser, Ala, Abu, Trp, DTrp, and Val, orthe N-methylated variant of Acc, Act,or Aib, or of said D- or L-aminoacid;

A33 is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-rnethylated variant of Acc, Aib,or Apc, or of said D- or L-amino acid;

A³⁴ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Gln, Asn, Glu, Asp, or the N-methylatedvariant of Acc, Aib, or Apc, or of said D- or L-amino acid;

A³⁵ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylated variant of Acc, Aib,or Apc, or of said D- or L-amino acid;

A³⁶ is Acc, Aic or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or theN-methylated variant of Acc, Aic, or Apc, or of said N or L-amino acid;

R¹ is OH or NH₂, (C₁-C₃₀)alkoxy, or NH—X⁶—CH₂-Z⁰, wherein X⁶ is a(C₁-C₁₂)hydrocarbon moiety, and Z⁰ is —H, —OH, —CO₂H or —C(O)NH₂;

R² and R³ each is, independently for each occurrence, selected from thegroup consisting of —H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl,(C₁-C₃₀)acyl, (C₂-C30)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl,aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl, substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)acyl, substituted(C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl, substitutedaryl(C₁-C₃₀)alkyl, and substituted aryl(C₁-C₃₀)acyl,

provided that when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted(C₂-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is —H,(C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted(C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl;

R⁴ and R⁵ each is, independently for each occurrence, selected from thegroup consisting of —H, (C₁-C₄₀)alkyl, (C₂-C₄₀)acyl,(C₁-C₃₀)alkylsulfonyl, and —C(NH)NH₂, provided that when R⁴ is(C₁-C₄₀)acyl, (C₁-C₃₀)alkylsulfonyl, or —C(NH)NH₂, then R⁵ is —H or(C₁-C₄₀)alkyl;

n is, independently for each occurrence, 1, 2, 3, 4 or 5; and

X¹, X², X³, X⁴, and X⁵ each is, independently for each occurrence,selected from thegroup consisting of —H, —F, —Cl, —Br, —I,(C₁-C₁₀)alkyl, substituted (C₁-C₁₀)alkyl, aryl, substituted aryl, —OH,—NH₂, —NO₂, and —CN;

provided that:

(a) said peptide comprises at least one amino acid selected from thegroup consisting of:

(i) Acc at A³, A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹⁵, A¹⁶, A¹⁷, A¹⁸, A²⁰, A²¹,A²², A²⁴, A²⁷, A²⁸, A²⁹, A³⁰, A³¹, A³², or A³⁴;

(ii) Act at A³, A⁷, A¹², A¹³, A²², A²³, or A³²;

(iii) Apc at A⁴, A⁷, A¹², A¹⁹ A²², A²⁵, A²⁶, A³³, A³⁵, or A³⁶;

(iv) Aib at A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹³, A¹⁵, A¹⁶; A¹⁸, A²², A²⁹ orA³²;

(v) Thz, Dmt, Dhp, Ktp, or Tic at A⁵, A⁸, or A¹⁴;

(vi) (3,4,5-F)Phe or (2,3,4,5,6-F)Phe at A²⁰, A²¹, A²⁶, A²⁷, or A³⁶;

(vii) 2Fua at A²⁰, A²¹A²⁶, or A²⁷;

(viii) Taz at A²⁰, A²¹, or A²⁶; and

(ix) 2Pal, 3Pal, 4Pal, 2Thi or 3Thi at A²⁶;

(b) if A³-A²¹ are deleted and (i) A22 is Aib or (ii) As is (3,4,5-F)Pheor (2,3,4,5,6-F)Phe, then A²⁷ is not 2Thi, Trp, 2Nal, or(X¹,X²,X³,X⁴,X⁵)Phe, wherein X¹ is p-chloro and X², X³, X⁴ and X⁵ eachis —H; and

(c) each amino acid A^(m) of formula (I) may be deleted only if A^(m-1)is deleted, wherein m is an integer ranging in value from 4-26,inclusive;

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the present invention is concerned withcompounds according to formula (I) as defined in paragraphs [021]-[075],wherein:

A³ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Ile, Leu, Nle, Tle, hLeu, Cha, Val, Ala, Nva,and Abu, or is deleted;

A⁴ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Lys, Arg, hArg, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted;

A⁵ is Inc or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, oris deleted;

A⁶ is Acc or a D- or L-amino acid selected from the list of amino acidsconsisting of Glu, Asp, Gln, Asn, Lys, Arg, Orn, Dab, Dap, and hArg, oris deleted;

A⁷ is Acc, Act, Aib, Apc, or Gly, or a D- or L-amino acid selected fromthe list of amino acids consisting of Ala, Abu, Val, and Nva, or isdeleted;

A⁸ is Inc or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, oris deleted;

A⁹ is Acc, Aib, or Gly or D- or L-Ala, or is deleted;

A¹⁰ is Acc or a D- or L-amino acid selected from the list of amino acidsconsisting of Glu, Asp, Gln, and Asn, or is deleted;

A¹¹ is Acc or a D- or L-amino acid selected from the list of amino acidsconsisting of Asp, Glu, Gln, and Asn, or is deleted;

A¹² is Acc, Act, Aib, or Apc, or a D- or L-amino acid selected from thelist of amino acids consisting of Ala, Gly, Abu, Val, and Nva, or isdeleted;

A¹³ is Acc, Act, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Ser, Thr, Ala, Abu, and Val, or is deleted;

A¹⁴ is Inc or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, oris deleted;

A¹⁵ is Acc or a D- or L-amino acid selected from the list of amino acidsconsisting of Glu, Asp, Gln, and Asn, or is deleted;

A¹⁶ is Acc or a D- or L-amino acid selected from the list of amino acidsconsisting of Glu, Asp, Gln, and Asn, or is deleted;

A¹⁷ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva,Abu, and Phe, or is deleted;

A¹⁸ is Aib or Acc, or a D- or L-amino acid selected from the list ofamino acids consisting of Asn, Gln, Glu, and Asp, or is deleted;

A¹⁹ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted;

A²⁰ is Acc or Aic, a D- or L-amino acid selected from the list of aminoacids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal,1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or is deleted;

A²¹ is Acc or Aic, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or isdeleted;

A²² is Acc, Act, Aib, Apc, or Gly, or a D- or L-amino acid selected fromthe list of amino acids consisting of Ala, Abu, Val, and Nva, or isdeleted;

A²³ is Acc, Act, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Ser, Thr, Ala, Abu, and Val, or is deleted;

A²⁴ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva,Abu, Trp, and Phe, or is deleted;

A²⁵ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted

A²⁶ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of His, 2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi,2Fua, HN—CH((CH₂)_(n)—N(R⁴R⁵))-C(O), and (X¹,X²,X³,X⁴,X⁵-)Phe, or isdeleted;

A²⁷ is Acc or Aic, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe;

A²⁸ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala,Nva, Abu, and Phe;

A²⁹ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Asn, Gln, Glu, Asp, and Trp;

A³⁰ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala,Nva, Abu, and Phe;

A³¹ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Val, Leu, Ile, Nle, Tle, hLeu, Cha, Ala, Nva,Abu, Trp, and Phe;

A³² is Acc, Act, or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Thr, Ser, Ala, Abu, Trp, and Val;

A³³ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O);

A³⁴ is Acc, Aib, Apc, or Glu, or a D- or L-amino acid selected from thelist of amino acids consisting of Gln, Asn, and Asp;

A³⁵ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵)—C(O); and

A³⁶ is Acc, Aic, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe;

or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment the present invention is concerned withcompounds according formula (I) as defined in paragraphs [021]-[075],wherein:

A³ is Ile, Leu, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Acc, or Aib, oris deleted;

A⁴ is Lys, Arg, hArg, Orn, Dab, Dap, Apc, Aib, Acc, orHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted;

A⁵ is Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, Oic, or Inc, or isdeleted;

A⁶ is Glu, Asp, Gln, Asn, Lys, Arg, Orn, Dab, Dap, hArg, or Acc, or isdeleted;

A⁷ is Ala, Aib, Gly, Abu, Val, Nva, Apc, Act, or Acc, or is deleted;

A⁸ is Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, Oic, or Inc, or isdeleted;

A⁹ is Gly, Ala, Aib, or Acc, or is deleted;

A¹⁰ is Glu, Asp, Gln, Asn, or Acc, or is deleted;

A¹¹ is Asp, Glu, Gln, Asn, or Acc, or is deleted;

A¹² is Ala, Aib, Gly, Abu, Val, Nva, Apc, Act, or Acc, or is deleted;

A¹³ is Ser, Thr, Aib, Act, Ala, Acc, Abu, or Val, or is deleted;

A¹⁴ is Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, Oic, or Inc, or isdeleted;

A¹⁵ is Glu, Asp, Gln, Asn, or Acc, or is deleted;

A¹⁶ is Glu, Asp, Gln, Asn, or Acc, or is deleted;

A¹⁷ is Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Acc, Aib, orPhe, or is deleted;

A¹⁸ is Asn, Gln, Glu, Asp, Aib, or Acc, or is deleted;

A¹⁹ is Arg, hArg, Lys, Orn, Dab, Dap, Apc, Aib, Acc, orHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted;

A²⁰ is Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha,2Pal, 3Pal, 4Pal, ( )X¹,X²,X³,X⁴,X⁵)Phe, Acc, or Aic, or is deleted;

A²¹ is Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha,2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Acc, or Aic, or is deleted;

A²² is Ala, Aib, Gly, Abu, Val, Nva, Apc, Act, Acc, or N-Me-Ala, or isdeleted;

A²³ is Ser, Thr, Aib, Act, Ala, Acc, Abu, Val, or DTrp, or is deleted;

A²⁴ is Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Acc, Aib, Trp,or Phe, or is deleted;

A²⁵ is Arg, hArg, Lys, Orn, Dab, Dap, Apc, Aib,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or Acc, or is deleted;

A²⁶ is His, 2Pal, D2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi, 2Fua, Apc, Aib,Acc, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or (X¹,X²,X³,X⁴,X⁵-)Phe, or isdeleted;

A²⁷ is Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha,2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Acc, or Aic;

A²⁸ is Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva, Abu, Acc, Aib,or Phe;

A²⁹ is Asn, Gln, Glu, Asp, Acc, Trp, or Aib;

A³⁰ is Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva, Abu, Acc, Aib,or Phe;

A³¹ is Val, Leu, Ile, Nle, Tle, hLeu, Cha, Ala, Nva, Abu, Acc, Aib, Trp,or Phe;

A³² is Thr, Ser, Aib, Act, Ala, Acc, Abu, Trp, DTrp, or Val;

A³³ is Arg, hArg, Lys, Orn, Dab, Dap, Apc, Aib,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or Acc;

A³⁴ is Gln, Asn, Glu, Asp, Acc, Aib, or Apc;

A³⁵ is Arg, hArg, Lys, Orn, Dab, Dap, Apc, Aib,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or Acc; and

A³⁶ is, Tyr, Phe,. hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal,: 1Nal, Cha,2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Acc, Aic, or Apc;

or a pharmaceutically acceptable salt thereof.

In a still more preferred embodiment the present invention is concernedwith compounds according formula (I) as defined in paragraphs[021]-[075], wherein:

A³ is Ile, Leu, Nle, Val, Acc, or Aib, or is deleted;

A⁴ is Lys, Arg, hArg, Orn, or Apc, or is deleted;

A⁵ is Pro, Thz, Dmt, 4Hyp, or 3Hyp, or is deleted;

A⁶ is Glu, Asp, Gln, or Acc, or is deleted;

A⁷ is Ala, Aib, Abu, Act, or Acc, or is deleted;

A⁸ is Pro, Thz, Dmt, 4Hyp, or 3Hyp, or is deleted;

A⁹ is Gly, Aib, or Acc, or is deleted;

A¹⁰ is Glu, Asp, Gln, or Acc or is deleted;

A¹¹ is Asp, Glu, Asn, or Acc or is deleted;

A¹² is Ala, Aib, Act, or Acc, or is deleted;

A¹³ is Ser, Thr, Aib, Act, or Acc, or is deleted;

A¹⁴ is Pro, Thz, Dmt, 4Hyp, or 3Hyp, or is deleted;

A¹⁵ is Glu, Asp, Gln, or Acc, or is deleted;

A¹⁶ is Glu, Asp, Gln, or Acc or is deleted;

A¹⁷ is Leu, Ile, Nle, Val, Acc, or Aib, or is deleted;

A¹⁸ is Asn, Gln, Asp, Aib, or Acc or is deleted;

A¹⁹ is Arg, hArg, Lys, or Apc, or is deleted;

A²⁰ is Tyr, Phe, 2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or isdeleted;

A²¹ is Tyr, Phe, 2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or isdeleted;

A²² is Ala, Aib, Abu, or Acc, or is deleted;

A²³ is Ser, Thr, Aib, Act, or Ala, or is deleted;

A²⁴ is Leu, Ile, Nle, Val, Acc, or Aib, or is deleted;

A²⁵ is Arg, hArg, Lys, or Apc, or is deleted;

A²⁶ is His, 2Pal, D2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi, Apc, or(X¹,X²,X³,X⁴,X⁵-)Phe, or is deleted;

A²⁷ is Tyr, Phe, 2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe or Acc;

A²⁸ is Leu, Ile, Nle,-Val, Acc or Aib;

A²⁹ is Asn, Gln, Asp, Acc or Aib;

A³⁰ is Leu, Ile, Nle, Val, Acc or Aib;

A³¹ is Val, Leu, Ile, Ala, Acc or Aib;

A³² is Thr, Ser, Aib, Act or Acc;

A³³ is Arg, hArg, Lys or Apc;

A³⁴ is Gln, Asn, Glu, Aib or Apc;

A³⁵ is Arg, hArg, Lys or Apc; and

A³⁶ is Tyr, Phe, 2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe or Apc;

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with compounds according formula (I) as defined in paragraphs[021]-[075], wherein:

A³ is Ile or Acc, or is deleted;

A⁴ is Lys or Apc, or is deleted;

A⁵ is Pro or is deleted;

A⁶ is Glu or Acc, or is deleted;

A⁷ is Ala, Act, or Acc, or is deleted;

A⁸ is Pro or is deleted;

A⁹ is Gly or Acc, or is deleted;

A¹⁰ is Glu or Acc, or is deleted;

A¹¹ is Asp or Acc, or is deleted;

A¹² is Ala, Act, or Acc, or is deleted;

A¹³ is Ser, Act, or Acc, or is deleted;

A¹⁴ is Pro or is deleted;

A¹⁵ is Glu or Acc, or is deleted;

A¹⁶ is Glu or Acc, or is deleted;

A¹⁷ is Leu or Acc, or is deleted;

A¹⁸ is Asn or Acc, or is deleted;

A¹⁹ is Arg or Apc, or is deleted;

A²⁰ is Tyr, (X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or is deleted;

A²¹ is Tyr, (X¹,X^(2,)X^(3,)X⁴ X⁵)Phe, or Acc, or is deleted;

A²² is Ala, Aib, or Acc, or is deleted;

A²³ is Ser or Act, or is deleted;

A²⁴ is Leu or Acc, or is deleted;

A²⁵ is Arg or Apc, or is deleted;

A²⁶ is His, 2Pal, D2Pal, 3Pal, 4Pal, Taz, Apc, or (X¹,X²,X³,X⁴,X⁵-)Phe,or is deleted;

A²⁷ is Tyr, (X¹,X²,X³,X⁴,X⁵)Phe, or Acc;

A²⁸ is Leu, or Acc;

A²⁹ is Asn or Acc;

A³⁰ is Leu or Acc;

A³¹ is Val, Leu or Acc;

A³² is Thr, Act, or Acc;

A³³ is Arg or Apc;

A³⁴ is Gln or Apc;

A³⁵ is Arg or Apc; and

A³⁶ is Tyr, (X¹,X²,X³,X⁴,X⁵)Phe, or Apc;

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with compounds according formula (I) as defined in paragraphs[021]-[075], wherein:

Acc is, independently for each occurrence, A5c or A6c; and

(X¹,X²,X³,X⁴,X⁵)Phe is, independently for each occurrence, (3,4,5-F)Pheor (2,3,4,5,6-F)Phe;

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned withcompounds according formula (I) as defined in paragraphs[021]-[075], wherein:

A³ is Ile or is deleted;

A⁴ is Lys or is deleted;

A⁶ is Glu or is deleted;

A⁷ is Ala or is deleted;

A⁹ is Gly or is deleted;

A¹⁰ is Glu or is deleted;

A¹¹ is Asp or is deleted;

A¹² is Ala or is deleted;

A¹³ is Ser or is deleted;

A¹⁴ is Pro or is deleted;

A¹⁵ is Glu or is deleted;

A¹⁶ is Glu or is deleted;

A¹⁷ is Leu or is deleted;

A¹⁸ is Asn or is deleted;

A¹⁹ is Arg or is deleted;

A²⁰ is Tyr or is deleted;

A²¹ is Tyr or is deleted;

A²² is Ala, Aib, or A5c, or is deleted;

A²³ is Ser or is deleted;

A²⁴ is Leu or A6c;

A²⁵ is Arg;

A²⁶ is His, 2Pal, D2Pal, 3Pal, 4Pal, or Taz;

A²⁷ is Tyr or (3,4,5-F)Phe;

A²⁸ is Leu, or A6c;

A²⁹ is Asn;

A³⁰ is Leu or A6c;

A³¹ is Val, Leu, A5c or A6c;

A³² is Thr;

A³³ is Arg;

A³⁴ is Gln; and

A³⁶ is Tyr;

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with a compound according formula (I) as defined in paragraphs[021]-[075], wherein said compound is:

((2,3,4,5,6-F)Phe²⁰)hPYY(3-36)NH₂; (SEQ ID NO. 31)

((2,3,4,5,6-F)Phe²¹)hPYY(3-36)NH₂; (SEQ ID NO. 32)

Ac-((2,3,4,5,6-F)Phe²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 33)

Ac-((2,3,4,5,6-F)Phe²⁶)hPYY(24-36)NH₂; (SEQ ID NO. 34)

((2,3,4,5,6-F)Phe²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 35)

Ac-((2,3,4,5,6-F)Phe²⁷)hPYY(22-36)NH₂; (SEQ ID NO. 36)

Ac-((2,3,4,5,6-F)Phe²⁷)hPYY(24-36)NH₂; (SEQ ID NO. 37)

((2,3,4,5,6-F)Phe²⁷)hPYY(3-36)NH₂; (SEQ ID NO. 38)

Ac-((2,3,4,5,6-F)Phe³⁶)hPYY(22-36)NH₂; (SEQ ID NO. 39)

Ac-((2,3,4,5,6-F)Phe³⁶)hPYY(24-36)NH₂; (SEQ ID NO. 40)

((2,3,4,5,6-F)Phe³⁶)hPYY(3-36)NH₂; (SEQ ID NO. 41)

((3,4,5-F)Phe²⁰)hPYY(3-36)NH₂; (SEQ ID NO. 42)

((3,4,5-F)Phe²¹)hPYY(3-36)NH₂; (SEQ ID NO. 43)

Ac-((3,4,5-F)Phe²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 44)

Ac-((3,4,5-F)Phe²⁶)hPYY(24-36)NH₂; (SEQ ID NO. 45)

((3,4,5-F)Phe²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 46)

Ac-((3,4,5-F)Phe²⁷)hPYY(22-36)NH₂; (SEQ ID NO. 15)

Ac-((3,4,5-F)Phe²⁷)hPYY(24-36)NH₂; (SEQ ID NO. 47)

((3,4,5-F)Phe²⁷)hPYY(3-36)NH₂; (SEQ ID NO. 12)

Ac-((3,4,5-F)Phe³⁶)hPYY(22-36)NH₂; (SEQ ID NO. 48)

Ac-((3,4,5-F)Phe36)hPYY(24-36)NH₂; (SEQ ID NO. 49)

((3,4,5-F)Phe36)hPYY(3-36)NH₂; (SEQ ID NO. 50)

Ac-(D2Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 26)

Ac-(2Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 27)

Ac-(2Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 18)

Ac-(3Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 14)

(3Pal²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 5)

Ac-(3Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 16)

Ac-(4Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 13)

Ac-(4Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 17)

Ac-(A5c²²)hPYY(22-36)NH₂ (SEQ ID NO. 4)

Ac-(A5c³¹)hPYY(22-36)NH₂; (SEQ ID NO. 24)

Ac-(A5c³¹)hPYY(24-36)NH₂; (SEQ ID NO. 51)

(A5c³¹)hPYY(3-36)NH₂ (SEQ ID NO. 3)

(A6c¹⁰)hPYY(3-36)NH₂; (SEQ ID NO. 52)

(A6c¹¹)hPYY(3-36)NH₂; (SEQ ID NO. 53)

(A6c¹²)hPYY(3-36)NH₂; (SEQ ID NO. 54)

(A6c¹³)hPYY(3-36)NH₂; (SEQ ID NO. 55)

(A6c¹⁵)hPYY(3-36)NH₂; (SEQ ID NO. 56)

(A6c¹⁶)hPYY(3-36)NH₂; (SEQ ID NO. 57)

(A6c¹⁷)hPYY(3-36)NH₂; (SEQ ID NO. 58)

(A6c¹⁸)hPYY(3-36)NH₂; (SEQ ID NO. 59)

(A6c²⁰)hPYY(3-36)NH₂; (SEQ ID NO. 60)

(A6c²¹)hPYY(3-36)NH₂; (SEQ ID NO. 61)

Ac-(A6c²²)hPYY(22-36)NH₂; (SEQ ID NO. 62)

(A6c²²)hPYY(3-36)NH₂; (SEQ ID NO. 63)

Ac-(A6c²⁴)hPYY(22-36)NH₂; (SEQ ID NO. 25)

Ac-(A6c²⁴)hPYY(24-36)NH₂; (SEQ ID NO. 64)

(A6C²⁴)hPYY(3-36)NH₂; (SEQ ID NO. 10)

Ac-(A6c²⁴, Leu³¹)hPYY(24-36)NH₂; (SEQ ID NO. 28)

Ac-(A6c²⁷)hPYY(22-36)NH₂; (SEQ ID NO. 65)

Ac-(A6c²⁷)hPYY(24-36)NH₂; (SEQ ID NO. 66)

(A6c²⁷)hPYY(3-36)NH₂; (SEQ ID NO. 67)

Ac-(A6c²⁸)hPYY(22-36)NH₂; (SEQ ID NO. 23)

Ac-(A6c²⁸)hPYY(24-36)NH₂; (SEQ ID NO. 68)

(A6c²⁸)hPYY(3-36)NH₂; (SEQ ID NO. 8)

Ac-(A6c²⁸, Leu³¹)hPYY(24-36)NH₂; (SEQ ID NO. 29)

Ac-(A6c²⁹)hPYY(22-36)NH₂; (SEQ ID NO. 69)

Ac-(A6c²⁹)hPYY(24-36)NH₂; (SEQ ID NO. 70)

(A6c²⁹)hPYY(3-36)NH₂; (SEQ ID NO. 71)

(A6c³)hPYY(3-36)NH₂; (SEQ ID NO. 72)

Ac-(A6c³⁰)hPYY(22-36)NH₂; (SEQ ID NO. 22)

Ac-(A6c³⁰)hPYY(24-36)NH₂; (SEQ ID NO. 73)

(A6c³⁰)hPYY(3-36)NH₂; (SEQ ID NO. 9)

Ac-(A6c³¹)hPYY(22-36)NH₂; .(SEQ ID NO. 21)

Ac-(A6c³¹)hPYY(24-36)NH₂; (SEQ ID NO. 30)

(A6c³¹)hPYY(3-36)NH₂; (SEQ ID NO. 74)

Ac-(A6c³²)hPYY(22-36)NH₂; (SEQ ID NO. 75)

Ac-(A6c³²)hPYY(24-36)NH₂; (SEQ ID NO. 76)

(A6c³²)hPYY(3-36)NH₂; (SEQ ID NO. 77)

(A6c⁶)hPYY(3-36)NH₂; (SEQ ID NO. 78)

(A6c⁷)hPYY(3-36)NH₂; (SEQ ID NO. 79)

(A6c⁹)hPYY(3-36)NH₂; (SEQ ID NO. 80)

(Act¹²)hPYY(3-36)NH₂; (SEQ ID NO. 81)

(Act¹³)hPYY(3-36)NH₂; (SEQ ID NO. 82)

Ac-(Act²³)hPYY(22-36)NH₂; (SEQ ID NO. 83)

(Act²³)hPYY(3-36)NH₂; (SEQ ID NO. 84)

Ac-(Act³²)hPYY(22-36)NH₂; (SEQ ID NO. 85)

Ac-(Act³²)hPYY(24-36)NH₂; (SEQ ID NO. 86)

(Act³²)hPYY(3-36)NH₂; (SEQ ID NO. 87)

(Act⁷)hPYY(3-36)NH₂; (SEQ ID NO. 88)

Ac-(Aib²²)hPYY(22-36)NH₂; (SEQ ID NO. 89)

(Aib²²)hPYY(3-36)NH₂; (SEQ ID NO. 11)

(Apc¹⁹)hPYY(3-36)NH₂; (SEQ ID NO. 90)

Ac-(Apc²⁵)hPYY(22-36)NH₂; (SEQ ID NO. 91)

Ac-(Apc²⁵)hPYY(24-36)NH₂; (SEQ ID NO. 92)

(Apc²⁵)hPYY(3-36)NH₂; (SEQ ID NO. 93)

Ac-(Apc²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 94)

Ac-(Apc²⁶)hPYY(24-36)NH₂; (SEQ ID NO. 95)

(Apc²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 96)

Ac-(Apc³³)hPYY(22-36)NH₂; (SEQ ID NO. 97)

Ac-(Apc³³)hPYY(24-36)NH₂; (SEQ ID NO. 98)

(Apc³³)hPYY(3-36)NH₂; (SEQ ID NO. 99)

Ac-(Apc³⁴)hPYY(22-36)NH₂; (SEQ ID NO. 100)

Ac-(Apc³⁴)hPYY(24-36)NH₂; (SEQ ID NO. 101)

(Apc³⁴)hPYY(3-36)NH₂; (SEQ ID NO. 102)

Ac-(Apc³⁵)hPYY(22-36)NH₂; (SEQ ID NO. 103)

Ac-(Apc³⁵)hPYY(24-36)NH₂; (SEQ ID NO. 104)

(Apc³⁵)hPYY(3-36)NH₂; (SEQ ID NO. 7)

Ac-(Apc³⁶)hPYY(22-36)NH₂; (SEQ ID NO. 105)

Ac-(Apc³⁶)hPYY(24-36)NH₂; (SEQ ID NO. 106)

(Apc³⁶)hPYY(3-36)NH₂; (SEQ ID NO. 107)

(Apc⁴)hPYY(3-36)NH₂; (SEQ ID NO. 108)

(Taz²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 6)

Ac-(Taz²⁶)hPYY(22-36)NH₂; or (SEQ ID NO. 20)

Ac-(Taz²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 19)

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with a compound according to the immediately foregoing list ofcompounds, wherein said compound is:

[A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)

Ac-[A5C²²]hPYY(22-36)NH₂ (SEQ ID NO. 4)

[3Pal²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 5)

[Taz²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 6)

[Apc³⁵]hPYY(3-36)NH₂; (SEQ ID NO. 7)

[A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8)

[A6C³⁰]hPYY(3-36)NH₂; (SEQ ID NO. 9)

[A6C²⁴]hPYY(3-36)NH₂; (SEQ ID NO. 10)

[Aib²²]hPYY(3-36)NH₂; (SEQ ID NO. 11)

[((3,4,5-F)Phe)²⁷]hPYY(3-36)NH₂; (SEQ ID NO. 12)

Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13)

Ac-[3Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 14)

Ac-[((3,4,5-F)Phe)²⁷]hPYY(22-36)NH₂; (SEQ ID NO. 15)

Ac-(3Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 16)

Ac-(4Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 17)

Ac-(2Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 18)

Ac-(Taz²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 19)

Ac-[Taz26]hPYY(22-36)NH₂; (SEQ ID NO. 20)

Ac-[A6c³¹]hPYY(22-36)NH₂; (SEQ ID NO. 21)

Ac-[A6c³⁰]hPYY(22-36)NH₂; (SEQ ID NO. 22)

Ac-[A6c²⁸]hPYY(22-36)NH₂; (SEQ ID NO. 23)

Ac-[A5c³¹]hPYY(22-36)NH₂; (SEQ ID NO. 24)

Ac-[A6C²⁴]hPYY(22-36)NH₂; (SEQ ID NO. 25)

Ac-[D2Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 26)

Ac-[2Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 27)

Ac-[A6C²⁴, Leu³¹]hPYY(24-36)NH₂; (SEQ ID NO. 28)

Ac-[A6C²⁸, Leu³¹]hPYY(24-36)NH₂;or (SEQ ID NO. 29)

Ac-[A6C³¹]hPYY(24-36)NH₂; (SEQ ID NO. 30)

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with a compound according to the immediately foregoing list ofcompounds, wherein said compound is:

[A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)

[3Pal²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 5)

[Taz²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 6)

[A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8)

[A6C²⁴]hPYY(3-36)NH₂; (SEQ ID NO. 10)

[Aib²²]hPYY(3-36)NH₂; (SEQ ID NO. 11)

[((3,4,5-F)Phe)²⁷]hPYY(3-36)NH₂; (SEQ ID NO. 12)

Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13)

Ac-[3Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 14)

Ac-(3Pal²⁶, Leu³¹)hPPY(24-36)NH₂; or (SEQ ID NO. 16)

Ac-(4Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 17)

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with a compound according to the immediately foregoing list ofcompounds, wherein saidcompound is:

[A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)

[3Pal²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 5)

[Taz²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 6)

[Apc³⁵]hPYY(3-36)NH₂; (SEQ ID NO. 7)

[A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8)

[A6C²⁴]hPYY(3-36)NH₂; (SEQ ID NO. 10)

[Aib²²]hPYY(3-36)NH₂; (SEQ ID NO. 11)

Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13)

Ac-[3Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 14)

Ac-(3Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 16)

Ac-(4Pal²⁶, Leu³¹)hPPY(24-36)NH₂; or (SEQ ID NO. 17)

or a pharmaceutically acceptable salt thereof.

In yet a still more preferred embodiment the present invention isconcerned with a compound according to the immediately foregoing list ofcompounds, wherein saidcompound is:

[A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)

[3Pal²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 5)

[A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8)

[A6C²⁴]hPYY(3-36)NH₂; or (SEQ ID NO. 10)

Ac-[4Pal26]hPYY(22-36)NH₂; (SEQ ID NO. 13)

or a pharmaceutically acceptable salt thereof.

In another aspect the present invention relates to a pharmaceuticalcomposition comprising one or more compounds as defined in paragraphs[021] through [0428], or apharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

In another aspect the present invention relates to a method ofdecreasing excess intestinal water and electrolyte secretion in a mammalin need thereof, said method comprising administering to said mammal aneffective amount of one or more compounds as defined in paragraphs [021]through [0428], or a pharmaceutically acceptable salt thereof.

In another aspect the present invention relates to a method ofregulating the proliferation of a cell type in a mammal in need thereof,said method comprising administering to said mammal an effective amountof one or more compounds as defined in paragraphs [021] through [0428],or a pharmaceutically acceptable salt thereof.

In preferred embodiments of the immediately preceding method said celltype is gastrointestinal cells and/or epithelial cells.

In another aspect the present invention relates to a method ofaugmenting nutrient transport in a mammal in need thereof, said methodcomprising administering to said mammal an effective amount of one ormore compounds as defined in paragraphs [021] through [0428], or apharmaceutically acceptable salt thereof.

In another aspect the present invention relates to a method ofregulating lipolysis in a mammal in need thereof, said method comprisingadministering to said mammal an effective amount of one or morecompounds as defined in paragraphs [021] through [0428], or apharmaceutically acceptable salt thereof.

In another aspect the present invention relates to a method ofregulating blood flow in a mammal in need thereof, said methodcomprising administering to said mammal an effective amount of one ormore compounds as defined in paragraphs [021] through [0428], or apharmaceutically acceptable salt thereof.

In another aspect the present invention relates to a method offacilitating weight loss, appetite decrease, weight maintenance,treating obesity, treating diabetes, treating complications of diabetesincluding retinopathy, or treating cardiovascular disorders in a mammalin need thereof, said method comprising administering to said mammal aneffective amount of one or more compounds as defined in paragraphs [021]through [0428], or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the immediately preceding method saidexcessive weight is a contributing factor to a disease or conditionincluding hypertension, diabetes, dyslipidemia, cardiovascular disease,gall stones, osteoarthritis and cancers.

In a more preferred embodiment of the immediately preceding method saidfacilitation of weight loss reduces the likelihood of such diseases orconditions or where said facilitation of weight loss comprises at leastpart of a treatment for such diseases or conditions.

In another aspect the present invention relates to a method ofantagonizing the effects of PYY(3-36) in a mammal in need thereof, saidmethod comprising administering to said mammal an effective amount ofone or more compounds as defined in paragraphs [021] through [0428]. ora pharmaceutically acceptable salt thereof, wherein said compound is aPYY antagonist.

In a preferred embodiment of the immediately preceding method saidantagonist effects in said mammal comprise facilitating weight gain,facilitating maintenance in weight, and/or facilitating appetiteincrease.

In more a preferred embodiment of the immediately preceding method saidfacilitating weight gain, facilitating maintenance in weight, and/orfacilitating appetite increase is indicated in a mammal having a diseaseor disorder, or under going a treatment, accompanied by weight loss.

In a still more preferred embodiment of the immediately preceding methodsaid diseases or disorders accompanied by weight loss include anorexia,bulimia, cancer cachexia, AIDS, wasting, cachexia, and wasting in frailelderly, or said treatment accompanied by weight loss compriseschemotherapy, radiation therapy, temporary or permanent immobilization,or dialysis.

In another aspect, this invention is directed to radiolabeled analogs offormula (I). Preferably the analogs have a tyrosine residue iodinated onthe phenyl ring, preferably at carbon position 3 or 5. The radioactiveiodine is preferably I¹²⁵ or I¹²³. The chemistry associated withiodinated tyrosine residues within peptides is well known in the art ofpeptide chemistry. (See, e.g., European Patent Application 0389180,herein incorporated by reference.) Accordingly, radiolabeled PYY analogscan be used for assays in respect of PYY receptors, e.g., forcompetitive binding assays, for imaging cells containing PYY receptors,etc.

In another aspect, this invention is directed to a pharmaceuticalcomposition comprising any one or more compounds as defined inparagraphs [0211] through [0428], or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

As set forth above and for convenience in describing this invention, theconventional and nonconventional abbreviations for the various aminoacids are used. They are familiar to those skilled in the art, but forclarity are listed below. All peptide sequences mentioned herein arewritten according to the usual convention whereby the N-terminal aminoacid is on the left and the C-terminal amino acid is on the right,unless noted otherwise.

Abbreviations (e.g. Ala) of amino acids in this disclosure stand for thestructure —NH—C(R)(R′)—CO—, wherein R and R′ each is, independently,hydrogen or the side chain of an amino acid (e.g., R═CH₃ and R′=H forAla), or R and R′ may be joined to form a ring system. The term“N-methylated variant” refers to the same structure wherein the hydrogenatom attached to the nitrogen atom is replaced by methyl; i.e.,—N(CH₃)—C(R)(R′)—CO—. For the N-terminal amino acid, the abbreviationstands for the structure ═N—C(R)(R′)—CO—, wherein “═” represents thebonds to R² and R³, defined herein.

A peptide of this invention is also denoted herein by another format,e.g., (A5C³¹)hPYY(3-36)NH₂, with the substituted amino acid(s) from thenatural sequence, (here, hPYY, i.e., human PYY) placed between the firstset of parentheses (e.g., A5c³¹ for Val³¹ in hPYY(3-36)). The numbersbetween the second set of parentheses refer to the number of amino acidspresent in the peptide. For example, “hPYY(22-36)” refers to amino acids22 through 36 of the peptide sequence for human PYY. The designation“NH₂” in, e.g., (A5C³¹)hPYY(3-36)NH₂, indicates that the C-terminus ofthe peptide is amidated. (A5C³¹)hPYY(3-36) or (A5C³¹)hPYY(3-36)-OH,indicates that the C-terminus is the free acid. Abu α-aminobutyric acidAcc 1-amino-1-cyclo(C₃—C₉)alkyl carboxylic acid A3c1-amino-1-cyclopropanecarboxylic acid A4c1-amino-1-cyclobutanecarboxylic acid A5c1-amino-1-cyclopentanecarboxylic acid A6c1-amino-1-cyclohexanecarboxylic acid Act4-amino-4-carboxytetrahydropyran

(i.e., the structure: Aib α-aminoisobutyric acid Aic2-aminoindan-2-carboxylic acid Ala or A alanine β-Ala beta-alanine

Apc denotes the structure: Arg or R arginine hArg homoarginine Asn or Nasparagine Asp or D aspartic acid Cha β-cyclohexylalanine Cys or Ccysteine Dab 2,4-diaminobutyric acid Dap 2,3-diaminopropionic acid Dhp3,4-dehydroproline Dmt 5,5-dimethylthiazolidine-4-carboxylic acid 2Fuaβ-(2-furyl)-alanine Gln or Q glutamine Glu or E glutamic acid Gly or Gglycine His or H histidine 3Hyp trans-3-hydroxy-L-proline (i.e., (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid) 4Hyp 4-hydroxyproline (i.e.,(2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid) Ile or I isoleucine Incindoline-2-carboxylic acid Inp isonipecotic acid Ktp 4-ketoproline Leuor L leucine hLeu homoleucine Lys or K lysine Met or M methionine 1Nalβ-(1-naphthyl)alanine 2Nal β-(2-naphthyl)alanine Nle norleucine Nvanorvaline Oic octahydroindole-2-carboxylic acid Orn ornithine 2Palβ-(2-pyridinyl)alanine 3Pal β-(3-pyridinyl)alanine 4Palβ-(4-pyridinyl)alanine Phe or F phenylalanine hPhe homophenylalanine(3,4,5-F)Phe 3,4,5-trifluorophenylalanine (2,3,4,5,6-F)Phe2,3,4,5,6-pentafluorophenylalanine Pip pipecolic acid Pro or P prolineSer or S serine

Taz β-(4-thiazolyl)alanine, i.e., 2Thi β-(2-thienyl)alanine 3Thiβ-(3-thienyl)alanine Thr or T threonine Thz thiazolidine-4-carboxylicacid Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Tletert-leucine Trp or W tryptophan Tyr or Y tyrosine Val or V valine

Certain other abbreviations used herein are defined as follows: Ac:acetyl Boc: tert-butyloxycarbonyl Bzl: benzyl DCM: dichloromethane DIC:N,N-diisopropylcarbodiimide DIEA: diisopropylethyl amine Dmab:4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)-amino}benzyl DMAP: 4-(dimethylamino)pyridine DMFN,N-dimethylformamide DNP: 2,4-dinitrophenyl Fmoc:Fluorenylmethyloxycarbonyl HBTU:2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphatecHex cyclohexyl HOAT:O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HOBt: 1-hydroxy-benzotriazole Mmt: 4-methoxytritylNMP: N-methylpyrrolidone Pbf:2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl tBu: tert-butyl TIS:triisopropylsilane TOS: tosyl trt trityl TFA: trifluoro acetic acidTFFH: tetramethylfluoroforamidinium hexafluorophosphate Z:benzyloxycarbonyl

“Alkyl” refers to a hydrocarbon group containing one or more carbonatoms, where multiple carbon atoms if present are joined by singlebonds. The alkyl hydrocarbon group may be straight-chain or contain oneor more branches or cyclic groups.

“Substituted alkyl” refers to an alkyl wherein one or more hydrogenatoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen, (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, —C₁₋₂ alkyl substituted with 1 to 6 halogens, (e.g., —CF₃, —C₂F₄,—C₂F₅, and the like), —OCH₃, —OCF₃, and —(CH₂)₀₋₄—COOH. In differentembodiments 1, 2, 3 or 4 substituents are present. The presence of—(CH₂)₀₋₄—COOH results in the production of an alkyl acid. Non-limitingexamples of alkyl acids containing, or consisting of, —(CH₂)₀₋₄—COOH,include 2-norbornane acetic acid, tert-butyric acid, 3-cyclopentylpropionic acid, and the like.

“Heteroalkyl” refers to an alkyl wherein one of more of the carbon atomsin the hydrocarbon group is/are replaced with one or more of thefollowing groups: amino, amido, —O—, or carbonyl.

“Substituted heteroalkyl” refers to a heteroalkyl wherein one or morehydrogen atoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen, (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, —C₁₋₂ alkyl substituted with 1 to 6 halogens, —CF₃, —OCH₃, —OCF₃,and —(CH₂)₀₋₄—COOH. In different embodiments 1, 2, 3 or 4 substituentsare present.

“Alkenyl” refers to a hydrocarbon group made up of two or more carbonswhere one or more carbon-carbon double bonds are present. The alkenylhydrocarbon group may be straight-chain or contain one or more branchesor cyclic groups.

“Substituted alkenyl” refers to an alkenyl wherein one or more hydrogensare replaced with one or more substituents selected from the groupconsisting of halogen (i.e., fluorine, chlorine, bromine, and iodine),—OH, —CN, —SH, —NH₂, —NHCH₃, —NO₂, —C₁₋₂ alkyl substituted with 1 to 6halogens, —CF₃, —OCH₃, —OCF₃, and —(CH₂)₀₋₄—COOH. In differentembodiments 1, 2, 3 or 4 substituents are present.

“Alkynyl” refers to a hydrocarbon group made up of two or more carbonswhere one or more carbon-carbon triple bonds are present. The alkynylhydrocarbon group may be straight-chain or contain one or more branchesor cyclic groups.

“Substituted alkynyl” refers to an alkynyl wherein one or more hydrogensare replaced with one or more substituents selected from the groupconsisting of halogen (i.e., fluorine, chlorine, bromine, and iodine),—OH, —CN, —SH, —NH₂, —NHCH₃, —NO₂, —C₁₋₂ alkyl substituted with 1 to 6halogens, —CF₃, —OCH₃, —OCF₃, and —(CH₂)₀₋₄—COOH. In differentembodiments 1, 2, 3 or 4 substituents are present.

“Aryl” refers to an optionally substituted aromatic group with at leastone ring having a conjugated pi-electron system, containing up to twoconjugated or fused ring systems. Aryl includes carbocyclic aryl,heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5 or 6membered ring. Preferred atoms for a heterocyclic aryl are one or moresulfur, oxygen, and/or nitrogen. Preferred examples of aryl includephenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and9-anthracene. Aryl substituents are selected from the group consistingof —C₁₋₄ alkyl, —C₁₋₄ alkoxy, halogen (i.e., fluorine; chlorine,bromine, and iodine), —OH, —CN, —SH, —NH₂, —NO₂, —C₁₋₂ alkyl substitutedwith 1 to 5 halogens, —CF₃, —OCF₃, and —(CH₂)₀₋₄—COOH. In differentembodiments the aryl contains 0, 1,2, 3, or 4 substituents.

“Arylalkyl” refers to an “alkyl” joined to an “aryl”.

“Acyl” refers to R″—C(O)—, where R″ is H, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, alkylaryl, substituted alklyaryl.

The compounds of the present invention can be provided in the form ofpharmaceutically acceptable salts. Examples of preferred salts are thoseformed with pharmaceutically acceptable organic acids, e.g., acetic,lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic,methanesulfonic, toluenesulfonic, trifluoroacetic, or pamoic acid, aswell as polymeric acids such as tannic acid or carboxymethyl cellulose,and salts with inorganic acids, such as hydrohalic acids (e.g.,hydrochloric acid), sulfuric acid, or phosphoric acid and the like. Anexample of a procedure for obtaining a pharmaceutically acceptable saltof a compound of this invention, more particularly the HCl salt, is asfollows. A purified peptide is dissolved in 0.1% HCl—H₂O, loaded onto asemipreparative reverse phase column (250×10 mm, 10 μM particle size,300A pore size), and eluted with a gradient of 0-100% 0.1% HCl—CH₃CN in0.1% HCl—H₂O. The fractions containing the peptide peak are combined,concentrated and lyophilized to obtain the HCl salt of the peptide.

A compound of the present invention can be made into compositions in theform of a liquid, pill, tablet, or capsule for oral administration; aliquid capable of being administered nasally as drops or spray or aliquid for intravenous, subcutaneous, parenteral, intraperitoneal orrectal administration. The therapeutic composition can also be in theform of an oil emulsion or dispersion in conjunction with a lipophilicsalt such as pamoic acid, or in the form of a biodegradablesustained-release composition for subcutaneous or intramuscularadministration.

The compounds of the invention exhibit a broad range of biologicalactivities related to their antisecretory and antimotility properties.While not wishing to be bound to any particular theory regarding themechanism of action, it is believed that the compounds suppressgastrointestinal secretions by direct interaction with epithelial cellsand/or by inhibiting secretion of hormones or neurotransmitters whichstimulate intestinal secretion. The compounds of the invention may alsocontrol intestinal blood flow which in turn may modulate intestinalhydrostatic pressure in favor of net water absorption.

The compounds of the invention are especially useful in the treatment ofany number of gastrointestinal disorders that are associated with excessintestinal electrlytes and water secretion as well as decreasedabsorption, e.g., infectious (e.g., viral or bacterial) diarrhea,inflammatory diarrhea, short bowel syndrome, or the diarrhea whichtypically occurs following surgical procedure, e.g., ileostomy (see e.g.Harrison's principles of Internal Medicine, McGraw Hill Inc., New York,12th ed.). Examples of infectious diarrhea include, without limitation,acute viral diarrhea, acute bacterial diarrhea (e.g., salmonella,campylobacter, and clostridium) or diarrhea due to protozoal infections,or travellers' diarrhea (e.g., Norwalk virus or rotavirus). Examples ofinflammatory diarrhea include, without limitation, malabsorptionsyndrome, tropical spue, chronic pancreatitis, Crohn's disease,diarrhea, and irritable bowel syndrome. It has also been discovered thatthe peptides of the invention can be used to treat an emergency orlife-threatening situation involving a gastrointestinal disorder, e.g.,after surgery or due to cholera. Furthermore, the compounds of theinvention can be used to treat intestinal dysfunction in patients withAcquired Immune Deficiency Syndrome (AIDS), especially during cachexia.

The compounds of the invention are also useful for inhibiting smallintestinal fluid and electrolyte secretion, and augmenting nutrienttransport, as well as increasing cell proliferation in thegastrointestinal tract, regulating lipolysis in, e.g., adipase tissueand regulating blood flow in a mammal.

The compounds of the invention are advantageous because they aretruncated versions of the natural PYY peptide; thus, the shorter peptidenot only facilitates easier synthesis and purification of the compounds,but also improves and reduces manufacturing procedures and expenses.Moreover, a shorter PYY compound is advantageous because such peptideswill interact solely with PYY receptors and not with homologousreceptors such as NPY Y1, Y3 and Y-5, thus minimizing unwanted agonistor antagonist side reactions.

The compounds of the invention can be and were produced using thetechniques disclosed in the examples herein as well as techniques thatare well known in the art. For example, a polypeptide region of a PYYanalog can be chemically or biochemically synthesized and modified.Examples of techniques for biochemical synthesis involving theintroduction of a nucleic acid into a cell and expression of nucleicacids are provided in Ausubel, Current Protocols in Molecular Biology,John Wiley, 1987-1998, and Sambrook et al., in Molecular Cloning, ALaboratory Manual, 2^(nd) Edition, Cold Spring Harbor Laboratory Press,1989. Techniques for chemical synthesis of polypeptides are also wellknown in the art. (See e.g., Vincent in Peptide and Protein DrugDelivery, New York, N.Y., Dekker, 1990; For example, the peptides ofthis invention can be prepared by standard solid phase peptidesynthesis. (See, e.g., Stewart, J. M., et al., Solid Phase Synthesis,2^(nd) Edition, Pierce Chemical Co., 1984.)

The substituents R² and R³ of the above generic formula may be attachedto thefree amine of the N-terminal amino acid by standard methods knownin the art. For example, alkyl groups, e.g., (C₁-C₃₀)alkyl, may beattached using reductive alkylation. Hydroxyalkyl groups, e.g.,(C₁-C₃₀)hydroxyalkyl, may also be attached using reductive alkylationwherein the free hydroxy group is protected with a t-butyl ester. Acylgroups, e.g., R″—C(O)—, may be attached by coupling the free acid, e.g.,R″COOH, to the free amine of the N-terminal amino acid by mixing thecompleted resin with 3 molar equivalents of both the free acid anddiisopropylcarbodiimide in methylene chloride for about one hour. If thefree acid contains a free hydroxy group, e.g., p-hydroxyphenylpropionicacid, then the coupling should be performed with an additional 3 molarequivalents of HOBT.

Peptides can be and were synthesized on an Applied Biosystems model 433Apeptide synthesizer (Foster City, Calif.) usingFluorenylmethyloxycarbonyl (Fmoc) chemistry. Rink Amide4-methylbenzylhydrylamine (MBHA) resin is used to obtain peptide amides(e.g. Example 1 below). Wang resin is used to obtain peptide acids. RinkAmide resin (substitution=0.72 mmol/g) or Wang resin (substitution=0.5mmol/g) is placed in thereaction vessel of the synthesizer. The aminoacids (4 equivalents) are sequentially coupledto the resin with thecoupling reagents of2-(1-H-benzotriazole-1-yl)-1,1,2,3-tetramethyluroniumhexafluorophosphate (HBTU) (3.8 equivalents), 1-hydroxy-benzotriazole(HOBT) (3.8 equivalents), and diisopropylethylamine (DIEA) (1 mL) inNMP.

When R¹ is NH—X⁶—CH₂—CONH₂, (i.e., Z⁰=CONH₂), the synthesis of thepeptide starts with Fmoc-HN—X⁶—CH₂—COOH which is coupled to the RinkAmide MBHA resin. If R¹ is NH—X⁶—CH₂—COOH, (i.e., Z⁰=COOH) the synthesisof the peptide starts with Fmoc-HN—X⁶—CH₂—COOH which is coupled to Wangresin. For this particular step, 4 molar equivalents of Fmoc-HN—X⁶—COOH,HBTU and HOBt and 10 molar equivalents of DIEA are used. The couplingtime is about 2 hours.

At the end of peptide synthesis, the Fmoc-group is removed. In somecases the free alpha amino group is then acylated with a suitableacylating agent. For example, the acylation may be carried out usingabout 2 equivalents of acetic anhydride until the ninhydrin test isnegative. (See example 2.)

The peptide-resin is then treated with a mixture of TFA, H₂O andtriisopropylsilane (TIS) (VNN, 9.5/0.85/0.8) for about 4 h. The resin isfiltered off and the filtrate is poured into ether. The precipitate iscollected by filtration and washed thoroughly with ether. This crudeproduct is dissolved in a mixed solvent system of acetonitrile andaqueous acetic acid and purified on a reverse-phase preparative HPLCsystem. The fractions are checked by analytical HPLC and thosecontaining pure product are pooled and lyophilized to dryness.

EXAMPLES Example 1 [A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)

The titled protected peptide was synthesized on an Applied Biosystemsmodel 433A peptide synthesizer (Foster City, Calif.) usingFluorenylmethyloxycarbonyl (Fmoc) chemistry. A Rink Amide4-methylbenzylhydrylamine (MBHA) resin (Novabiochem., San Diego, Calif.)with substitution of 0.72 mmol/g was used. The Fmoc amino acids(AnaSpec, San Jose, Calif.) used were Fmco-Tyr(tBu)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-A5C—Fmoc-1-aminocyclopentanecarboxylic acid), Fmoc-Leu-OH,Fmoc-Asn(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH,Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Asp(tBu)-OH, Fmoc-Gly-OH,Fmoc-Lys(Boc)-OH, and Fmoc-Ile-OH. The synthesis was carried out on a0.25 mmol scale. The Fmoc groups were removed by treatment with 20%piperidine in N-methylpyrrolidone (NMP) for 30 min. In each couplingstep, the Fmoc amino acid (4 eq, 1 mmol) was first pre-activated in 2 mLsolution of 0.45M 2-(1-H-benzotriazole-1-yl)-1,1,2,3-tetramethyluroniumhexafluorophosphate/1-hydroxy-benzotriazole (HBTU/HOBT) in NMP. Thisactivated amino acid ester, 1 mL of diisopropylethylamine (DIEA) and 1mL of NMP were added to the resin. The ABI 433A peptide synthesizer wasprogrammed to perform the following reaction cycle: (1) washing withNMP, (2) removing Fmoc protecting group with 20% piperidine in NMP for30 min, (3) washing with NMP, (4) coupling with pre-activated Fmoc aminoacid for 1 h. The resin was coupled successively according to thesequence of the title peptide. After the peptide chain was assembled,the Fmoc group was removed and the resin was washed completely by usingN,N-dimethylformamide (DMF) and dichloromethane (DCM).

At the end of the assembly of the peptide chain, the peptide-resin wastransferred to a reaction vessel on a shaker and treated with a mixtureof TFA, H₂O and triisopropylsilane (TIS) (9.5 mL/0.85 mL/0.8 mL) for 4h. The resin was filtered off and the filtrate was poured into 200 mL ofether. The precipitate was collected by filtration and washed thoroughlywith ether. This crude product was dissolved in a mixture ofacetonitrile and aqueous acetic acid solution and purified on areverse-phase preparative HPLC system with a column (4×43 cm) of C₁₈DYNAMAX-100 A⁰ (Varian, Walnut Creek, Calif.). The column was elutedover approximately 1 hour using a linear gradient of 95% A:5% B to 55%A:45% B, where A was 0.1% TFA in water and B was 0.1% TFA inacetonitrile. The fractions were checked by analytical HPLC and thosecontaining pure product were pooled and lyophilized to dryness. Puritywas assayed using HPLC and found to be approximately 97.6%.Electro-spray ionization mass spectrometry (ESI-MS) analysis gave themolecular weight at 4060.7 (in agreement with the calculated molecularweight of 4061.51).

Example 2 Ac-[A5C²²]hPYY(22-36)NH₂ (SEQ ID NO 4)

The titled peptide was synthesized and purified substantially accordingto the procedures described in Example 1. For the last coupling step, 2mL of NMP solution containing 94 μL of Ac₂O, 44 μL of DIEA and 4 mg ofHOBt was used to cap the N-terminal amino group with an acetylfunctional group. The coupling time for this step was 30 min. Purity ofthe final acylated peptide was 99.9% based upon HPLC analysis.Electro-spray ionization mass spectrometry (ESI MS) analysis gave themolecular weight at 1970.9 (in agreement with the calculated molecularweight of 1971.29).

Examples 3-28

Examples 3-28 can be and were prepared substantially according to theprocedures disclosed in Examples 1 and 2, above. SEQ Purity Mol. Wt.Mol. Wt. Ex. Compound ID NO. (HPLC) (ESI-MS) (Calculated)  3.[3Pal²⁶]hPYY(3-36)NH₂  5 99.9 4060.0 4060.5  4. [Taz²⁶]hPYY(3-36)NH₂  695.6 4066.2 4066.6  5. [Apc³⁵]hPYY(3-36)NH₂  7 94.1 4019.0 4019.5  6.[A6C²⁸]hPYY(3-36)NH₂  8 96.8 4062.0 4061.5  7. [A6C³⁰]hPYY(3-36)NH₂  999.9 4062.0 4061.5  8. [A6C²⁴]hPYY(3-36)NH₂ 10 96.5 4062.0 4061.5  9.[Aib²²]hPYY(3-36)NH₂ 11 97.7 4064.0 4063.5 10.[(3,4,5-F)Phe²⁷]hPYY(3-36)NH₂ 12 99.9 4087.2 4087.5 11.Ac-[4Pal²⁶]hPYY(22-36)NH₂ 13 99.9 1942.0 1942.3 12.Ac-[3Pal²⁶]hPYY(22-36)NH₂ 14 99.0 1941.7 1942.3 13.Ac-[(3,4,5-F)Phe²⁷]hPYY(22-36)NH₂ 15 100 1969.2 1969.2 14. Ac-(3Pal²⁶,Leu³¹)hPPY(24-36)NH₂ 16 97.2 1797.7 1798.1 15. Ac-(4Pal²⁶,Leu³¹)hPPY(24-36)NH₂ 17 97.0 1797.7 1798.1 16. Ac-(2Pal²⁶,Leu³¹)hPPY(24-36)NH₂ 18 94.8 1797.9 1798.1 17. Ac-(Taz²⁶,Leu³¹)hPPY(24-36)NH₂ 19 97.9 1803.4 1804.2 18. Ac-[Taz²⁶]hPYY(22-36)NH₂20 97.9 1948.3 1948.3 19. Ac-[A6c³¹]hPYY(22-36)NH₂ 21 99.9 1957.2 1957.320. Ac-[A6c³⁰]hPYY(22-36)NH₂ 22 99.0 1942.9 1943.2 21.Ac-[A6c²⁸]hPYY(22-36)NH₂ 23 99.9 1942.8 1943.2 22.Ac-[A5c³¹]hPYY(22-36)NH₂ 24 99.9 1942.6 1943.2 23.Ac-[A6C²⁴]hPYY(22-36)NH₂ 25 99.9 1943.2 1943.2 24.Ac-[D2Pal²⁶]hPYY(22-36)NH₂ 26 96.0 1941.9 1942.3 25.Ac-[2Pal²⁶]hPYY(22-36)NH₂ 27 99.6 1941.8 1942.3 26. Ac-[A6C²⁴,Leu³¹]hPYY(24-36)NH₂ 28 97.5 1798.9 1799.1 27. Ac-[A6C²⁸,Leu³¹]hPYY(24-36)NH₂ 29 96.3 1798.9 1799.1 28. Ac-[A6C³¹]hPYY(24-36)NH₂30 98.8 1798.9 1799.1

Examples 29-56 Radioligand Binding Assay

Human neuroblastoma cell lines, SK-N-MC and SK-N-BE2 (American TypeCulture Collection, Rockville, Md.) were cultured in EMEM mediacontaining 10% fetal calf serum and 5% chicken embryo extract in ahumidified atmosphere (37° C.) of 90% air and 10% CO₂.

For the in vitro Y1 and Y2 radioligand binding assays, the appropriatecells (SK-N-MC for Y1; SK-N-BE2 for Y2) were harvested, homogenized(Polytron, setting 6, 15 sec) in ice-cold 50 mM Tris-HCl (Buffer A), andcentrifuged twice at 39,000×g (10 min), with an intermediateresuspension in fresh buffer. The final pellets were resuspended inapproximately 20 ml of 50 mM Tris-HCl containing 5.0 mM MgCl₂, 0.1 mg/mlbacitracin, and 0.1% BSA (Buffer B), and held on ice for the receptorbinding assay.

For assay, aliquots (0.4 ml) of the foregoing suspensions were incubatedwith 0.05 ml of 0.05 nM [¹²⁵I-Leu³¹, Pro³⁴]PYY (Y1 receptor) or[¹²⁵I]PYY(3-36) (Y2 receptor), (each ˜2200 Ci/mmol, New England Nuclear)in Buffer B, with or without 0.05 ml a solution (ranging from 0.01 nM-1000 nM) of an unlabeled competing peptide. After a 120 min incubation(25° C.), the bound radioligand was separated from the free by rapidfiltration through GF/C filters, previously soaked in 0.3%polyethyleneimine. The filters were then washed three times with 5-mlaliquots of ice-cold Buffer A. Specific binding was defined as the totalPYY radioligand bound minus that bound in the presence of 1 μM unlabeledPYY. Inhibition constants (K₁,) were calculated using the well-knownCheng-Prusoff equation.

Each of the compounds of Examples 1-28 was subjected to the immediatelyforegoing radioligand assay and was found to have, for the Y2 receptor,a K₁ of under 1000 nM, and for the Y1 receptor, a K₁ of under 2000 nM.Nearly all of the compounds of Examples 1-18 had K₁ values of under 30nM for the Y2 receptor and under 300 nM for the Y1 receptor.

Antisecretory Effects; Intestinal Water and Sodium Absorption

The antisecretory effects and the effects on intestinal water and sodiumabsorption may be studied using techniques well known to one of skill inthe art. For example, antisecretory effects may be investigated usingthe jejunal mucosa/short-circuit current (SCC) technique as described byCox et al., J. Physiol. 398:65, 1988, (“Cox”) and detailed in U.S. Pat.No. 6,046,167, (“U.S. '167”) while intestinal water and sodiumabsorption may be investigated using the ileal Thiry-Vela fistulaetechnique, also detailed in U.S. '167. The contents of each of Cox andU.S. '167 are incorporated herein by reference in their entirety.

In the practice of the method of the present invention, an effectiveamount of any one of the peptides of this invention or a combination ofany of the peptides of this invention or a pharmaceutically acceptablesalt thereof, is administered via any of the usual and acceptablemethods known in the art, either singly or in combination. The compoundsor compositions can thus be administered orally (e.g., buccal cavity),sublingually, parenterally (e.g., intramuscularly, intravenously, orsubcutaneously), rectally (e.g., by suppositories or washings),transdermally (e.g., skin electroporation) or by inhalation (e.g., byaerosol), and inthe form or either solid, liquid or gaseous dosage,including tablets and suspensions. The administration can be conductedin a single unit dosage form with continuous therapy or in a single dosetherapy ad libitum.

Thus, the method of the present invention is practiced when relief ofsymptoms is specifically required or perhaps imminent. Alternatively,the method of the present invention is effectively practiced ascontinuous or prophylactic treatment.

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids or gases; thus, the compositions can takethe form of tablets, pills, capsules, suppositories, powders,enterically coated or other protected formulations (e.g. binding onion-exchange resins or packaging in lipid-protein vesicles), sustainedrelease formulations, solutions, suspensions, elixirs, aerosols, and thelike. The carrier can be selected from the various oils including thoseof petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers,particularly (when isotonic with the blood) for injectable solutions.For example, formulations for intravenous administration comprisesterile aqueous solutions of the active ingredient(s) which are preparedby dissolving solid active ingredient(s) in water to produce an aqueoussolution, and rendering the solution sterile. Suitable pharmaceuticalexcipients include starch, cellulose, talc, glucose, lactose, talc,gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodiumstearate, glycerol monostearate, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Thecompositions may be subjected to conventional pharmaceutical additivessuch as preservatives, stabilizing agents, wetting or emulsifyingagents, salts for adjusting osmotic pressure, buffers and the like.Suitable pharmaceutical carriers and their formulation are described inRemington's Pharmaceutical Sciences by E. W. Martin. Such compositionswill, in any event, contain an effective amount of the active compoundtogether with a suitable carrier so as to prepare the proper dosage formfor proper administration to the recipient.

The dose of the compound of the present invention for treating theabove-mentioned disorders varies depending upon the manner ofadministration, the age and the body weight of the subject, and thecondition of the subject to be treated, and ultimately will be decidedby the attending physician or veterinarian. Such an amount of the activecompound as determined by the attending physician or veterinarian isreferred to herein, and in the claims, as an “effective amount”. Thus, atypical administration is oral administration or parenteraladministration. The daily dose in the case of oral administration istypically in the range of 0.1 to 100 mg/kg body weight, and the dailydose in the case of parenteral administration is typically in the rangeof 0.001 to 50 mg/kg body weight.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention as defined by the appended claims. Those skilled in the artwill recognize or be able to ascertain using no more than routineexperimentation, many equivalents to the specific embodiments of theinvention described specifically herein. Such equivalents are intendedto be encompassed in the scope of the claims. Also, all documentsreferred to herein are incorporated by reference into the presentapplication as though fully set forth herein.

1. A compound according to formula (I):(R², R³)A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A₁₀-A_(11-A)¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A₃₄-A³⁵-A³⁶-R¹  (I)wherein: A³ is Acc, Act, or Aib, or a D- or L-amino acid selected fromthe list of amino acids consisting of Ile, Leu, Nle, Tle, hLeu, Cha,Val, Ala, Nva, and Abu, or the N-methylated variant of Acc, Act, or Aib,or of said D- or L-amino acid, or is deleted; A⁴ is Aib, Acc, or Apc, ora D- or L-amino acid selected from the list of amino acids consisting ofLys, Arg, hArg, Orn, Dab, Dap, and HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or theN-methylated variant of Aib, Acc, or Apc, or of said D- or L-amino acid,or is deleted; A⁵ is Inc, or a D- or L-amino acid selected from the listof amino acids consisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip,Tic, and Oic, or the N-methylated variant of Inc or of said D- orL-amino acid, or is deleted; A⁶ is Acc or Aib, or a D- or L-amino acidselected from the list of amino acids consisting of Glu, Asp, Gln, Asn,Lys, Arg, Orn, Dab, Dap, and hArg, or the N-methylated variant of Acc orAib, or of said D- or L-amino acid, or is deleted; A⁷ is Acc, Act, Aib,Apc, or Gly, or a D- or L-amino acid selected from the list of aminoacids consisting of Ala, Abu, Val, and Nva, or the N-methylated variantof Acc, Act, Aib, Apc, or Gly, or of said D- or L-amino acid, or isdeleted; A⁸ is Inc or a D- or L-amino acid selected from the list ofamino acids consisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic,and Oic, or the N-methylated variant of Inc or of said D- or L-aminoacid, or is deleted; A⁹ is Acc, Aib, or Gly, or D- or L-Ala, or theN-methylated variant of Acc, Aib, Gly, or D- or L-Ala, or is deleted;A¹⁰ is Acc or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Glu, Asp, Gln, and Asn, or the N-methylatedvariant of Acc or Aib, or of said D- or L-amino acid, or is deleted; A¹¹is Acc or Aib, or a D- or L-amino acid selected from the list of aminoacids consisting of Asp, Glu, Gln, and Asn, or the N-methylated variantof Acc or Aib, or of said D- or L-amino acid, or is deleted; A¹² is Acc,Act, Aib, Apc, or Gly, or a D- or L-amino acid selected from the list ofamino acids consisting of Ala, Abu, Val, and Nva, or the N-methylatedvariant of Acc, Act, Aib, Apc, or Gly, or of said D- or L-amino acid, oris deleted; A¹³ is Acc, Aib, or Act, or a D- or L-amino acid selectedfrom the list of amino acids consisting of Ser, Thr, Ala, Abu, and Val,or the N-methylated variant of Acc, Aib, or Act, or of said D- orL-amino acid, or is deleted; A¹⁴ is Inc or a D- or L-amino acid selectedfrom the list of amino acids consisting of Pro, Thz, Dmt, Dhp, Ktp,4Hyp, 3Hyp, Pip, Tic, and Oic, or the N-methylated variant of Inc or ofsaid D- or L-amino acid, or is deleted; A¹⁵ is Acc or Aib, or a D- orL-amino acid selected from the list of amino acids consisting of Glu,Asp, Gln, and Asn, or the N-methylated variant of Acc or Aib, or of saidD- or L-amino acid, or is deleted; A¹⁶ is Acc or Aib, or a D- or L-aminoacid selected from the list of amino acids consisting of Glu, Asp, Gln,and Asn, or the N-methylated variant of Acc or Aib, or of said D- orL-amino acid, or is deleted; A¹⁷ is Acc or Aib, or a D- or L-amino acidselected from the list of amino acids consisting of Leu, Ile, Nle, Tle,hLeu, Cha, Val, Ala, Nva, Abu, and Phe, or the N-methylated variant ofAcc or Aib, or of said D- or L-amino acid, or is deleted; A¹⁸ is Acc orAib, or a D- or L-amino acid selected from the list of amino acidsconsisting of Asn, Gln, Glu, and Asp, or the N-methylated variant of Accor Aib, or of said D- or L-amino acid, or is deleted; A¹⁹ is Acc, Aib,or Apc, or a D- or L-amino acid selected from the list of amino acidsconsisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylated variant of Acc, Aib,or Apc, or of said D- or L-amino acid, or is deleted; A²⁰ is Acc or Aic,or a D- or L-amino acid selected from the list of amino acids consistingof Tyr, Phe, hPhe, 2Thi, 3Thi, Taz; 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal,3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or the N-methylated variant of Accor Aic, or of said D- or L-amino acid, or is deleted; A²¹ is Acc or Aic,or a D- or L-amino acid selected from the list of amino acids consistingof Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal,3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or the N-methylated variant of Accor Aic, or of said D- or L-amino acid, or is deleted; A²² is Acc, Act,Aib, Apc, or Gly, or a D- or L-amino acid selected from the list ofamino acids consisting of Ala, Aib, Abu, Val, and Nva, or theN-methylated variant of Acc, Act, Aib, Apc, or Gly, or of said D- orL-amino acid, or is deleted; A²³ is Acc, Act, or Aib, or a D- or L-aminoacid selected from the list of amino acids consisting of Ser, Thr, Ala,Abu, and Val, or the N-methylated variant of Acc, Act, or Aib, or ofsaid D- or L-amino acid, or is deleted; A²⁴ is Acc or Aib, or a D- orL-amino acid selected from the list of amino acids consisting of Leu,Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Trp, and Phe, or theN-methylated variant of Acc or Aib, or of said D- or L-amino acid, or isdeleted; A²⁵ is Acc, Aib, or Aib, or a D- or L-amino acid selected fromthe list of amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap,Aib, and HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylated variant ofAcc, Aib, or Aib, or of said D- or L-amino acid, or is deleted; A²⁶ isAcc, Aib, or Apc, or a D- or L-amino acid selected from the list ofamino acids consisting of His, 2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi, 2Fua,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), and (X¹,X²,X³,X⁴,X⁵-)Phe, or theN-methylated variant of Acc, Aib, or Apc, or of said D- or L-amino acid,or is deleted; A²⁷ is Acc or Aic, or a D- or L-amino acid selected fromthe list of amino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz,2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe,or the N-methylated variant of Acc or Aic or of said D- or L-amino acid;A²⁸ is Acc or Aib, a m or L-amino acid selected from the list of aminoacids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva,Abu, and Phe, or the N-methylated variant of Acc or Aib, or of said D-or L-amino acid; A²⁹ is Acc or Aib, or a D- or L-amino acid selectedfrom the list of amino acids consisting of Asn, Gln, Glu, Asp, and Trp,or the N-methylated variant of Acc or Aib, or of said D- or L-aminoacid; A³⁰ is Acc or Aib, or a D- or L-amino acid selected from the listof amino acids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val,Ala, Nva, Abu, and Phe or the N-methylated variant of Acc or Aib, or ofsaid D- or L-amino acid; A³¹ is Acc or Aib, or a D- or L-amino acidselected from the list of amino acids consisting of Val, Leu, Ile, Nle,Tle, hLeu, Cha, Ala, Nva, Abu, Trp, and Phe, or the N-methylated variantof Acc or Aib, or of said D- or L-amino acid; A³² is Acc, Act, or Aib,or a D- or L-amino acid selected from the list of amino acids consistingof Thr, Ser, Ala, Abu, Trp, DTrp, and Val, or the N-methylated variantof Acc, Act, or Aib, or of said D- or L-amino acid; A³³ is Acc, Aib, orApc, or a D- or L-amino acid selected from the list of amino acidsconsisting of Arg, hArg,. Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)N(R⁴R⁵))—C(O), or the N-methylated variant of Acc, Aib,or Apc, or of said D- or L-amino acid; A³⁴ is Acc, Aib, or Apc, or a D-or L-amino acid selected from the list of amino acids consisting of Gln,Asn, Glu, Asp, or the N-methylated variant of Acc, Aib, or Apc, or ofsaid D- or L-amino acid; A³⁵ is Acc, Aib, or Apc, or a D- or L-aminoacid selected from the list of amino acids consisting of Arg, hArg, Lys,Orn, Dab, Dap, and HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or the N-methylatedvariant of Acc, Aib, or Apc, or of said D- or L-amino acid; A³⁶ is Acc,Aic or Apc, or a D- or L-amino acid selected from the list of aminoacids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal,1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or theN-methylated variant of Acc, Aic, or Apc, or of said D- or L-amino acid;R¹ is OH or NH₂, (C₁-C₃₀)alkoxy, or NH—X⁶—CH₂-Z⁰, wherein X⁶ is a(C₁-C₁₂)hydrocarbon moiety, and Z⁰ is —H, —OH, —CO₂H or —C(O)NH₂; R² andR³ each is, independently for each occurrence, selected from the groupconsisting of —H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl,(C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl,substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₂-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl,substituted aryl(C₁-C₃₀)alkyl, and substituted aryl(C₁-C₃₀)acyl,provided that when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted(C₂-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, R³ is —H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl,substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted(C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl; R⁴ and R⁵ each is,independently for each occurrence, selected from the group consisting of—H, (C₁-C₄₀)alkyl, (C₂-C₄₀)acyl, (C₁-C₃₀)alkylsulfonyl, and —C(NH)NH₂,provided that when R⁴ is (C₁-C₄₀)acyl, (C₁-C₃₀)alkylsulfonyl, or—C(NH)NH₂, then R⁵ is —H or (C₁-C₄₀)alkyl; n is, independently for eachoccurrence, 1, 2, 3, 4 or 5; and X¹, X², X³, X⁴, and X⁵ each is,independently for each occurrence, selected from the group consisting of—H, —F, —Cl, —Br, —I, (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)alkyl, aryl,substituted aryl, —OH, —NH₂, —NO₂, and —CN; provided that: (a) saidpeptide comprises at least one amino acid selected from the groupconsisting of: (i) Acc at A³, A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹², A¹⁵, A¹⁶, A¹⁷,A¹⁸, A²⁰, A²¹, A²², A²⁴, A²⁷, A²⁸ , A²⁹, A³⁰, A³¹, A³², or A³⁴; (ii) Actat A³, A⁷, A¹², A¹³, A²², A²³, or A³²; (iii) Apc at A⁴, A⁷, A¹², A¹⁹,A²², A²⁵, A²⁶, A³³, A³⁵, or A³⁶; (iv) Aib at A⁶, A⁷, A⁹, A¹⁰, A¹¹, A¹²,A¹³, A¹⁵, A¹⁶, A¹⁸, A²², A²⁹, or A³²; (v) Thz, Dmt, Dhp, Ktp, or Tic atA⁵, A⁸, or A¹⁴; (vi) (3,4,5-F)Phe or (2,3,4,5,6-F)Phe at A²⁰, A²¹, A²⁶,A²⁷, or A³⁶; (vii) 2Fua at A²⁰, A²¹, A²⁶, or A²⁷; (viii) Taz at A²⁰,A²¹, or A²⁶; and (ix) 2Pal, 3Pal, 4Pal, 2Thi or 3Thi at A²⁶; (b) ifA³-A²¹ are deleted and (i) A²² is Aib or (ii) A³⁶ is (3,4,5-F)Phe or(2,3,4,5,6-F)Phe, then A²⁷ is not 2Thi, Trp, 2Nal, or(X¹,X²,X³,X⁴,X⁵)Phe, wherein X¹ is P-chloro and X², X³, X⁴ and X⁵ eachis —H; and (c) each amino acid A^(m) of formula (I) may be deleted onlyif A^(m-1) is deleted, wherein m is an integer ranging in value from4-26, inclusive; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1, wherein: A³ is Acc or Aib, or a D- orL-amino acid selected from the list of amino acids consisting of Ile,Leu, Nle, Tle, hLeu, Cha, Val, Ala, Nva, and Abu, or is deleted; A⁴ isAcc, Aib, or Apc, or a D- or L-amino acid selected from the list ofamino acids consisting of Lys, Arg, hArg, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵)—C(O), or is deleted; A⁵ is Inc or a D- orL-amino acid selected from the list of amino acids consisting of Pro,Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, or is deleted; A⁶ isAcc or a D- or L-amino acid selected from the list of amino acidsconsisting of Glu, Asp, Gln, Asn, Lys, Arg, Orn, Dab, Dap, and hArg, oris deleted; A⁷ is Acc, Act, Aib, Apc, or Gly, or a D- or L-amino acidselected from the list of amino acids consisting of Ala, Abu, Val, andNva, or is deleted; A⁸ is Inc or a D- or L-amino acid selected from thelist of amino acids consisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp,Pip, Tic, and Oic, or is deleted; A⁹ is Acc, Aib, or Gly or D- or L-Ala,or is deleted; A¹⁰ is Acc or a D- or L-amino acid selected from the listof amino acids consisting of Glu, Asp, Gln, and Asn, or is deleted; A¹¹is Acc or a D- or L-amino acid selected from the list of amino acidsconsisting of Asp, Glu, Gln, and Asn, or is deleted; A¹² is Acc, Act,Aib, or Apc, or a D- or L-amino acid selected from the list of aminoacids consisting of Ala, Gly, Abu, Val, and Nva, or is deleted; A¹³ isAcc, Act, or Aib, or a D- or L-amino acid selected from the list ofamino acids consisting of Ser, Thr, Ala, Abu, and Val, or is deleted;A¹⁴ is Inc or a D- or L-amino acid selected from the list of amino acidsconsisting of Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, and Oic, oris deleted; A¹⁵ is Acc or a D- or L-amino acid selected from the list ofamino acids consisting of Glu, Asp, Gln, and Asn, or is deleted; A¹⁶ isAcc or a D- or L-amino acid selected from the list of amino acidsconsisting of Glu, Asp, Gln, and Asn, or is deleted; A¹⁷ is Acc or Aib,or a D- or L-amino acid selected from the list of amino acids consistingof Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, and Phe, or isdeleted; A¹⁸ is Aib or Acc, or a D- or L-amino acid selected from thelist of amino acids consisting of Asn, Gln, Glu, and Asp, or is deleted;A¹⁹ is Acc, Aib, or Apc, or a D- or L-amino acid selected from the listof amino acids consisting of Arg, hArg, Lys, Orn, Dab, Dap, andHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted; A²⁰ is Acc or Aic, a D- orL-amino acid selected from the list of amino acids consisting of Tyr,Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal, 3Pal,4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or is deleted; A²¹ is Acc or Aic, or a D-or L-amino acid selected from the list of amino acids consisting of Tyr,Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal, 3Pal,4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe, or is deleted; A²² is Acc, Act, Aib, Apc,or Gly, or a D- or L-amino acid selected from the list of amino acidsconsisting of Ala, Abu, Val, and Nva, or is deleted; A²³ is Acc, Act, orAib, or a D- or L-amino acid selected from the list of amino acidsconsisting of Ser, Thr, Ala, Abu, and Val, or is deleted; A²⁴ is Acc orAib, or a D- or L-amino acid selected from the list of amino acidsconsisting of Leu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Trp,and Phe, or is deleted; A²⁵ is Acc, Aib, or Apc, or a D- or L-amino acidselected from the list of amino acids consisting of Arg, hArg, Lys, Orn,Dab, Dap, and HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted A²⁶ is Acc,Aib, or Apc, or a D- or L-amino acid selected from the list of aminoacids consisting of His, 2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi, 2Fua,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), and (X¹,X²,X³,X⁴,X⁵-)Phe, or is deleted;A²⁷ is Acc or Aic, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe; A²⁸ is Accor Aib, or a D- or L-amino acid selected from the list of amino acidsconsisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva, Abu,and Phe; A²⁹ is Acc or Aib, or a D- or L-amino acid selected from thelist of amino acids consisting of Asn, Gln, Glu, Asp, and Trp; A³⁰ isAcc or Aib, or a D- or L-amino acid selected from the list of aminoacids consisting of Leu, Ile, Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva,Abu, and Phe; A³¹ is Acc or Aib, or a D- or L-amino acid selected fromthe list of amino acids consisting of Val, Leu, Ile, Nle, Tle, hLeu,Cha, Ala, Nva, Abu, Trp, and Phe; A³² is Acc, Act, or Aib, or a D- orL-amino acid selected from the list of amino acids consisting of Thr,Ser, Ala, Abu, Trp, and Val; A³³ is Acc, Aib, or Apc, or a D- or L-aminoacid selected from the list of amino acids consisting of Arg, hArg, Lys,Orn, Dab, Dap, and HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O); A³⁴ is Acc, Aib, Apc,or Glu, or a D- or L-amino acid selected from the list of amino acidsconsisting of Gln, Asn, and Asp; A³⁵ is Acc, Aib, or Apc, or a D- orL-amino acid selected from the list of amino acids consisting of Arg,hArg, Lys, Orn, Dab, Dap, and HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O); and A³⁶ isAcc, Aic, or Apc, or a D- or L-amino acid selected from the list ofamino acids consisting of Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp,2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal, and (X¹,X²,X³,X⁴,X⁵)Phe; or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 2, wherein: A³ is Ile, Leu, Nle, Tle, hLeu, Cha, Val, Ala, Nva,Abu, Acc, or Aib, or is deleted; A⁴ is Lys, Arg, hArg, Orn, Dab, Dap,Apc, Aib, Acc, or HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted; A⁵ isPro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic, Oic, or Inc, or isdeleted; A⁶ is Glu, Asp, Gln, Asn, Lys, Arg, Orn, Dab, Dap, hArg, orAcc, or is deleted; A⁷ is Ala, Aib, Gly, Abu, Val, Nva, Apc, Act, orAcc, or is deleted; A⁸ is Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip, Tic,Oic, or Inc, or is deleted; A⁹ is Gly, Ala, Aib, or Acc, or is deleted;A¹⁰ is Glu, Asp, Gln, Asn, or Acc, or is deleted; A¹¹ is Asp, Glu, Gln,Asn, or Acc, or is deleted; A¹² is Ala, Aib, Gly, Abu, Val, Nva, Apc,Act, or Acc, or is deleted; A¹³ is Ser, Thr, Aib, Act, Ala, Acc, Abu, orVal, or is deleted; A¹⁴ is Pro, Thz, Dmt, Dhp, Ktp, 4Hyp, 3Hyp, Pip,Tic, Oic, or Inc, or is deleted; A¹⁵ is Glu, Asp, Gln, Asn, or Acc, oris deleted; A¹⁶ is Glu, Asp, Gln, Asn, or Acc, or is deleted; A¹⁷ isLeu, Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Acc, Aib, or Phe, oris deleted; A¹⁸ is Asn, Gln, Glu, Asp, Aib, or Acc, or is deleted; A¹⁹is Arg, hArg, Lys, Orn, Dab, Dap, Apc, Aib, Acc, orHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or is deleted; A²⁰ is Tyr, Phe, hPhe,2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal,(X¹,X²,X³,X⁴,X⁵)Phe, Acc, or Aic, or is deleted; A²¹ is Tyr, Phe, hPhe,2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal, 3Pal, 4Pal,(X¹,X²,X³,X⁴,X⁵)Phe, Acc, or Aic, or is deleted; A²² is Ala, Aib, Gly,Abu, Val, Nva, Apc, Act, Acc, or N-Me-Ala, or is deleted; A²³ is Ser,Thr, Aib, Act, Ala, Acc, Abu, Val, or DTrp, or is deleted; A²⁴ is Leu,Ile, Nle, Tle, hLeu, Cha, Val, Ala, Nva, Abu, Acc, Aib, Trp, or Phe, oris deleted; A²⁵ is Arg, hArg, Lys, Orn, Dab, Dap, Apc, Aib,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or Acc, or is deleted; A²⁶ is His, 2Pal,D2Pal, 3Pal, 4Pal, Taz, 2Thi, 3Thi, 2Fua, Apc,. Aib, Acc,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or (X¹,X²,X³,X⁴,X⁵-)Phe, or is deleted;A²⁷ is Tyr, Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha,2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Acc, or Aic; A²⁸ is Leu, Ile,Nle, Tle, hLeu, Trp, Cha, Val, Ala, Nva, Abu, Acc, Aib, or Phe; A²⁹ isAsn, Gln, Glu, Asp, Acc, Trp, or Aib; A³⁰ is Leu, Ile, Nle, Tle, hLeu,Trp, Cha, Val, Ala, Nva, Abu, Acc, Aib, or Phe; A³¹ is Val, Leu, Ile,Nle, Tle, hLeu, Cha, Ala, Nva, Abu, Acc, Aib, Trp, or Phe; A³² is Thr,Ser, Aib, Act, Ala, Acc, Abu, Trp, DTrp, or Val; A³³ is Arg, hArg, Lys,Orn, Dab, Dap, Apc, Aib, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), or Acc; A³⁴ isGln, Asn, Glu, Asp, Acc, Aib, or Apc; A³⁵ is Arg, hArg, Lys, Orn, Dab,Dap, Apc, Aib, HN—CH((CH₂)_(n)—N(R⁴R⁵)—C(O), or Acc; and A³⁶ is Tyr,Phe, hPhe, 2Thi, 3Thi, Taz, 2Fua, Trp, 2Nal, 1Nal, Cha, 2Pal, 3Pal,4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, Acc, Aic, or Apc; or a pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 3, wherein: A³is Ile, Leu, Nle, Val, Acc, or Aib, or is deleted; A⁴ is Lys, Arg, hArg,Orn, or Apc, or is deleted; A⁵ is Pro, Thz, Dmt, 4Hyp, or 3Hyp, or isdeleted; A⁶ is Glu, Asp, Gln, or Acc, or is deleted; A⁷ is Ala, Aib,Abu, Act, or Acc, or is deleted; A⁸ is Pro, Thz, Dmt, 4Hyp, or 3Hyp, oris deleted; A⁹ is Gly, Aib, or Acc, or is deleted; A¹⁰ is Glu, Asp, Gln,or Acc or is deleted; A¹¹ is Asp, Glu, Asn, or Acc or is deleted; A¹² isAla, Aib, Act, or Acc, or is deleted; A¹³ is Ser, Thr, Aib, Act, or Acc,or is deleted; A¹⁴ is Pro, Thz, Dmt, 4Hyp, or 3Hyp, or is deleted; A¹⁵is Glu, Asp, Gln, or Acc, or is deleted; A¹⁶ is Glu, Asp, Gln, or Acc oris deleted; A¹⁷ is Leu, Ile, Nle, Val, Acc, or Aib, or is deleted; A¹⁸is Asn, Gln, Asp, Aib, or Acc or is deleted; A¹⁹ is Arg, hArg, Lys, orApc, or is deleted; A²⁰ is Tyr, Phe, 2Pal, 3Pal, 4Pal,(X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or is deleted; A²¹ is Tyr, Phe, 2Pal, 3Pal,4Pal, (X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or is deleted; A²² is Ala, Aib, Abu,or Acc, or is deleted; A²³ is Ser, Thr, Aib, Act, or Ala, or is deleted;A²⁴ is Leu, Ile, Nle, Val, Acc, or Aib, or is deleted; A²⁵ is Arg, hArg,Lys, or Apc, or is deleted; A²⁶ is His, 2Pal, D2Pal, 3Pal, 4Pal, Taz,2Thi, 3Thi, Apc, or (X¹,X²,X³,X⁴,X⁵-)Phe, or is deleted; A²⁷ is Tyr,Phe, 2Pal, 3Pal, 4Pal, (X¹,X²,X³,X⁴,X⁵)Phe or Acc; A²⁸ is Leu, Ile, Nle,Val, Acc or Aib; A²⁹ is Asn, Gln, Asp, Acc or Aib; A³⁰ is Leu, Ile, Nle,Val, Acc or Aib; A³¹ is Val, Leu, Ile, Ala, Acc or Aib; A³² is Thr, Ser,Aib, Act or Acc; A³³ is Arg, hArg, Lys or Apc; A³⁴ is Gln, Asn, Glu, Aibor Apc; A³⁵ is Arg, hArg, Lys or Apc; and A³⁶ is Tyr, Phe, 2Pal, 3Pal,4Pal, (X¹,X²,X³,X⁴,X⁵)Phe or Apc; or a pharmaceutically acceptable saltthereof.
 5. A compound according to claim 4, wherein: A³ is Ile or Acc,or is deleted; A⁴ is Lys or Apc, or is deleted; A⁵ is Pro or is deleted;A⁶ is Glu or Acc, or is deleted; A⁷ is Ala, Act, or Acc, or is deleted;A⁸ is Pro or is deleted; A⁹ is Gly or Acc, or is deleted; A¹⁰ is Glu orAcc, or is deleted; A¹¹ is Asp or Acc, or is deleted; A¹² is Ala, Act,or Acc, or is deleted; A¹³ is Ser, Act, or Acc, or is deleted; A¹⁴ isPro or is deleted; A¹⁵ is Glu or Acc, or is deleted; A¹⁶ is Glu or Acc,or is deleted; A¹⁷ is Leu or Acc, or is deleted; A¹⁸ is Asn or Acc, oris deleted; A¹⁹ is Arg or Apc, or is deleted; A²⁰ is Tyr,(X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or is deleted; A²¹ is Tyr,(X¹,X²,X³,X⁴,X⁵)Phe, or Acc, or is deleted; A²² is Ala, Aib, or Acc, oris deleted; A²³ is Ser or Act, or is deleted; A²⁴ is Leu or Acc, or isdeleted; A²⁵ is Arg or Apc, or is deleted; A²⁶ is His, 2Pal, D2Pal,3Pal, 4Pal, Taz, Apc, or (X¹,X²,X³,X⁴,X⁵-)Phe, or is deleted; A²⁷ isTyr, (X¹,X²,X³,X⁴,X⁵)Phe, or Acc; A²⁸ is Leu, or Acc; A²⁹ is Asn or Acc;A³⁰ is Leu or Acc; A³¹ is Val, Leu or Acc; A³² is Thr, Act, or Acc; A³³is Arg or Apc; A³⁴ is Gln or Apc; A³⁵ is Arg or Apc; and A³⁶ is Tyr,(X¹,X²,X³,X⁴,X⁵)Phe, or Apc; or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 5, wherein: Acc is,independently for each occurrence, A5c or A6c; and (X¹,X²,X³,X⁴,X⁵)Pheis, independently for each occurrence, (3,4,5-F)Phe or (2,3,4,5,6-F)Phe;or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 6, wherein: A³ is Ile or is deleted; A⁴ is Lys or is deleted;A⁶ is Glu or is deleted; A⁷ is Ala or is deleted; A⁹ is Gly or isdeleted; A¹⁰ is Glu or is deleted; A¹¹ is Asp or is deleted; A¹² is Alaor is deleted; A¹³ is Ser or is deleted; A¹⁴ is Pro or is deleted; A¹⁵is Glu or is deleted; A¹⁶ is Glu or is deleted; A¹⁷ is Leu or isdeleted; A¹⁸ is Asn or is deleted; A¹⁹ is Arg or is deleted; A²⁰ is Tyror is deleted; A²¹ is Tyr or is deleted; A²² is Ala, Aib, or A5c, or isdeleted; A²³ is Ser or is deleted; A²⁴ is Leu or A6c; A²⁵ is Arg; A²⁶ isHis, 2Pal, D2Pal, 3Pal, 4Pal, or Taz; A²⁷ is Tyr or (3,4,5-F)Phe; A²⁸ isLeu, or A6c; A²⁹ is Asn; A³⁰ is Leu or A6c; A³¹ is Val, Leu, A5c or A6c;A³² is Thr; A³³ is Arg; A³⁴ is Gln; and A³⁶ is Tyr; or apharmaceutically acceptable salt thereof.
 8. A compound according toclaim 6, wherein said compound is according to the formula:((2,3,4,5,6-F)Phe²⁰)hPYY(3-36)NH₂; (SEQ ID NO. 31)((2,3,4,5,6-F)Phe²¹)hPYY(3-36)NH₂; (SEQ ID NO. 32)Ac-((2,3,4,5,6-F)Phe²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 33)Ac-((2,3,4,5,6-F)Phe²⁶)hPYY(24-36)NH₂; (SEQ ID NO. 34)((2,3,4,5,6-F)Phe²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 35)Ac-((2,3,4,5,6-F)Phe²⁷)hPYY(22-36)NH₂; (SEQ ID NO. 36)Ac-((2,3,4,5,6-F)Phe²⁷)hPYY(24-36)NH₂; (SEQ ID NO. 37)((2,3,4,5,6-F)Phe²⁷)hPYY(3-36)NH₂; (SEQ ID NO. 38)Ac-((2,3,4,5,6-F)Phe³⁶)hPYY(22-36)NH₂; (SEQ ID NO. 39)Ac-((2,3,4,5,6-F)Phe³⁶)hPYY(24-36)NH₂; (SEQ ID NO. 40)((2,3,4,5,6-F)Phe³⁶)hPYY(3-36)NH₂; (SEQ ID NO. 41)((3,4,5-F)Phe²⁰)hPYY(3-36)NH₂; (SEQ ID NO. 42)((3,4,5-F)Phe²¹)hPYY(3-36)NH₂; (SEQ ID NO. 43)Ac-((3,4,5-F)Phe²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 44)Ac-((3,4,5-F)Phe²⁶)hPYY(24-36)NH₂; (SEQ ID NO. 45)((3,4,5-F)Phe²⁶)hPYY(3-36)NH₂; (SEQ ID NO. 46)Ac-((3,4,5-F)Phe²⁷)hPYY(22-36)NH₂; (SEQ ID NO. 15)Ac-((3,4,5-F)Phe²⁷)hPYY(24-36)NH₂; (SEQ ID NO. 47)((3,4,5-F)Phe²⁷)hPYY(3-36)NH₂; (SEQ ID NO. 12)Ac-((3,4,5-F)Phe³⁶)hPYY(22-36)NH₂; (SEQ ID NO. 48)Ac-((3,4,5-F)Phe³⁶)hPYY(24-36)NH₂; (SEQ ID NO. 49)((3,4,5-F)Phe³⁶)hPYY(3-36)NH₂; (SEQ ID NO. 50)Ac-(D2Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 26) Ac-(2Pal²⁶)hPYY(22-36)NH₂;(SEQ ID NO. 27) Ac-(2Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 18)Ac-(3Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 14) (3Pal²⁶)hPYY(3-36)NH₂; (SEQID NO. 5) Ac-(3Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 16)Ac-(4Pal²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 13) Ac-(4Pal²⁶,Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 17) Ac-(A5c²²)hPYY(22-36)NH₂ (SEQ IDNO. 4) Ac-(A5c³¹)hPYY(22-36)NH₂; (SEQ ID NO. 24)Ac-(A5c³¹)hPYY(24-36)NH₂; (SEQ ID NO. 51) (A5c³¹)hPYY(3-36)NH₂ (SEQ IDNO. 3) (A6c¹⁰)hPYY(3-36)NH₂; (SEQ ID NO. 52) (A6c¹¹)hPYY(3-36)NH₂; (SEQID NO. 53) (A6c¹²)hPYY(3-36)NH₂; (SEQ ID NO. 54) (A6c¹³)hPYY(3-36)NH₂;(SEQ ID NO. 55) (A6c¹⁵)hPYY(3-36)NH₂; (SEQ ID NO. 56)(A6c¹⁶)hPYY(3-36)NH₂; (SEQ ID NO. 57) (A6c¹⁷)hPYY(3-36)NH₂; (SEQ ID NO.58) (A6c¹⁸)hPYY(3-36)NH₂; (SEQ ID NO. 59) (A6c²⁰)hPYY(3-36)NH₂; (SEQ IDNO. 60) (A6c²¹)hPYY(3-36)NH₂; (SEQ ID NO. 61) Ac-(A6c²²)hPYY(22-36)NH₂;(SEQ ID NO. 62) (A6c²²)hPYY(3-36)NH₂; (SEQ ID NO. 63)Ac-(A6c²⁴)hPYY(22-36)NH₂; (SEQ ID NO. 25) Ac-(A6c²⁴)hPYY(24-36)NH₂; (SEQID NO. 64) (A6C²⁴)hPYY(3-36)NH₂; (SEQ ID NO. 10) Ac-(A6c²⁴, Leu³¹)hPYY(24-36)NH₂; (SEQ ID NO. 28) Ac-(A6c²⁷)hPYY(22-36)NH₂; (SEQ ID NO.65) Ac-(A6c²⁷)hPYY(24-36)NH₂; (SEQ ID NO. 66) (A6c²⁷)hPYY(3-36)NH₂; (SEQID NO. 67) Ac-(A6c²⁸)hPYY(22-36)NH₂; (SEQ ID NO. 23)Ac-(A6c²⁸)hPYY(24-36)NH₂; (SEQ ID NO. 68) (A6c²⁸)hPYY(3-36)NH₂; (SEQ IDNO. 8) Ac-(A6c²⁸, Leu³¹)hPYY(24-36)NH₂; (SEQ ID NO. 29)Ac-(A6c²⁹)hPYY(22-36)NH₂; (SEQ ID NO. 69) Ac-(A6c²⁹)hPYY(24-36)NH₂; (SEQID NO. 70) (A6c²⁹)hPYY(3-36)NH₂; (SEQ ID NO. 71) (A6c³)hPYY(3-36)NH₂;(SEQ ID NO. 72) Ac-(A6c³⁰)hPYY(22-36)NH₂; (SEQ ID NO. 22)Ac-(A6c³⁰)hPYY(24-36)NH₂; (SEQ ID NO. 73) (A6c³⁰)hPYY(3-36)NH₂; (SEQ IDNO. 9) Ac-(A6c³¹)hPYY(22-36)NH₂; (SEQ ID NO. 21)Ac-(A6c³¹)hPYY(24-36)NH₂; (SEQ ID NO. 30) (A6c³¹)hPYY(3-36)NH₂; (SEQ IDNO. 74) Ac-(A6c³²)hPYY(22-36)NH₂; (SEQ ID NO. 75)Ac-(A6c³²)hPYY(24-36)NH₂; (SEQ ID NO. 76) (A6c³²)hPYY(3-36)NH₂; (SEQ IDNO. 77) (A6c⁶)hPYY(3-36)NH₂; (SEQ ID NO. 78) (A6c⁷)hPYY(3-36)NH₂; (SEQID NO. 79) (A6c⁹)hPYY(3-36)NH₂; (SEQ ID NO. 80) (Act¹²)hPYY(3-36)NH₂;(SEQ ID NO. 81) (Act¹³)hPYY(3-36)NH₂; .(SEQ ID NO. 82)Ac-(Act)hPYY(22-36)NH₂; (SEQ ID NO. 83) (Act²³)hPYY(3-36)NH₂; (SEQ IDNO. 84) Ac-(Act³²)hPYY(22-36)NH₂; (SEQ ID NO. 85)Ac-(Act³²)hPYY(24-36)NH₂; (SEQ ID NO. 86) (Act³²)hPYY(3-36)NH₂; (SEQ IDNO. 87) (Act⁷)hPYY(3-36)NH₂; (SEQ ID NO. 88) Ac-(Aib²²)hPYY(22-36)NH₂;(SEQ ID NO. 89) (Aib²²)hPYY(3-36)NH₂; (SEQ ID NO. 11)(Apc¹⁹)hPYY(3-36)NH₂; (SEQ ID NO. 90) Ac-(Apc²⁵)hPYY(22-36)NH₂; (SEQ IDNO. 91) Ac-(Apc²⁵)hPYY(24-36)NH₂; (SEQ ID NO. 92) (Apc²⁵)hPYY(3-36)NH₂;(SEQ ID NO. 93) Ac-(Apc²⁶)hPYY(22-36)NH₂; (SEQ ID NO. 94)Ac-(Apc²⁶)hPYY(24-36)NH₂; (SEQ ID NO. 95) (Apc²⁶)hPYY(3-36)NH₂; (SEQ IDNO. 96) Ac-(Apc³³)hPYY(22-36)NH₂; (SEQ ID NO. 97)Ac-(Apc³³)hPYY(24-36)NH₂; (SEQ ID NO. 98) (Apc³³)hPYY(3-36)NH₂; (SEQ IDNO. 99) Ac-(Apc³⁴)hPYY(22-36)NH₂; (SEQ ID NO. 100)Ac-(Apc³⁴)hPYY(24-36)NH₂; (SEQ ID NO. 101) (Apc³⁴)hPYY(3-36)NH₂; (SEQ IDNO. 102) Ac-(Apc³⁵)hPYY(22-36)NH₂; (SEQ ID NO. 103)Ac-(Apc³⁵)hPYY(24-36)NH₂; (SEQ ID NO. 104) (Apc³⁵)hPYY(3-36)NH₂; (SEQ IDNO. 7) Ac-(Apc³⁶)hPYY(22-36)NH₂; (SEQ ID NO. 105)Ac-(Apc³⁶)hPYY(24-36)NH₂; (SEQ ID NO. 106) (Apc³⁶)hPYY(3-36)NH₂; (SEQ IDNO. 107) (Apc⁴)hPYY(3-36)NH₂; (SEQ ID NO. 108) (Taz²⁶)hPYY(3-36)NH₂;(SEQ ID NO. 6) Ac-(Taz²⁶)hPYY(22-36)NH₂; or (SEQ ID NO. 20) Ac-(Taz²⁶,Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 19) or a pharmaceutically acceptablesalt thereof.
 9. A compound according to claim 8, wherein said compoundis according to the formula: [A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)Ac-[A5C²²]hPYY(22-36)NH₂ (SEQ ID NO. 4) [3Pal²⁶]hPYY(3-36)NH₂; (SEQ IDNO. 5) [Taz²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 6) [Apc³⁵]hPYY(3-36)NH₂; (SEQID NO. 7) [A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8) [A6C³⁰]hPYY(3-36)NH₂;(SEQ ID NO. 9) [A6C²⁴]hPYY(3-36)NH₂; (SEQ ID NO. 10)[Aib²²]hPYY(3-36)NH₂; (SEQ ID NO. 11) [((3,4,5-F)Phe)²⁷]hPYY(3-36)NH₂;(SEQ ID NO. 12) Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13)Ac-[3Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 14)Ac-[((3,4,5-F)Phe)²⁷]hPYY(22-36)NH₂; (SEQ ID NO. 15) Ac-(3Pal²⁶,Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 16) Ac-(4Pal²⁶, Leu³¹)hPPY(24-36)NH₂;(SEQ ID NO. 17) Ac-(2Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 18)Ac-(Taz²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 19)Ac-[Taz²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 20) Ac-[A6c³¹]hPYY(22-36)NH₂; (SEQID NO. 21) Ac-[A6c³⁰]hPYY(22-36)NH₂; (SEQ ID NO. 22)Ac-[A6c²⁸]hPYY(22-36)NH₂; (SEQ ID NO. 23) Ac-[A5c³¹]hPYY(22-36)NH₂; (SEQID NO. 24) Ac-[A6C²⁴]hPYY(22-36)NH₂; (SEQ ID NO. 25)Ac-[D2Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 26) Ac-[2Pal²⁶]hPYY(22-36)NH₂;(SEQ ID NO. 27) Ac-[A6C²⁴, Leu³¹]hPYY(24-36)NH₂; (SEQ ID NO. 28)Ac-[A6C²⁸, Leu³¹]hPYY(24-36)NH₂; or (SEQ ID NO. 29)Ac-[A6C³¹]hPYY(24-36)NH₂; (SEQ ID NO. 30) or a pharmaceuticallyacceptable salt thereof.
 10. A compound according to claim 9, whereinsaid compound is: [A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)[3Pal²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 5) [Taz²⁶]hPYY(3-36)NH₂; (SEQ ID NO.6) [A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8) [A6C²⁴]hPYY(3-36)NH₂; (SEQ IDNO. 10) [Aib²²]hPYY(3-36)NH₂; (SEQ ID NO. 11)[((3,4,5-F)Phe)²⁷]hPYY(3-36)NH₂; (SEQ ID NO. 12)Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13) Ac-[3Pal²⁶]hPYY(22-36)NH₂;(SEQ ID NO. 14) Ac-(3Pal²⁶, Leu³¹)hPPY(24-36)NH₂; or (SEQ ID NO. 16)Ac-(4Pal²⁶, Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 17) or a pharmaceuticallyacceptable salt thereof.
 11. A compound according to claim 9, whereinsaid compound is: [A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3)[3Pal²⁶]hPYY(3-36)NH₂; (SEQ ID NO. 5) [Taz²⁶]hPYY(3-36)NH₂; (SEQ ID NO.6) [Apc³⁵]hPYY(3-36)NH₂; (SEQ ID NO. 7) [A6C²⁸]hPYY(3-36)NH₂; (SEQ IDNO. 8) [A6C²⁴]hPYY(3-36)NH₂; (SEQ ID NO. 10) [Aib²²]hPYY(3-36)NH₂; (SEQID NO. 11) Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13)Ac-[3Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 14) Ac-(3Pal²⁶,Leu³¹)hPPY(24-36)NH₂; or (SEQ ID NO. 16) Ac-(4Pal²⁶,Leu³¹)hPPY(24-36)NH₂; (SEQ ID NO. 17) or a pharmaceutically acceptablesalt thereof.
 12. A compound according to claim 9, wherein said compoundis: [A5C³¹]hPYY(3-36)NH₂ (SEQ ID NO. 3) [3Pal²⁶]hPYY(3-36)NH₂; (SEQ IDNO. 5) [A6C²⁸]hPYY(3-36)NH₂; (SEQ ID NO. 8) [A6C²⁴]hPYY(3-36)NH₂; or(SEQ ID NO. 10) Ac-[4Pal²⁶]hPYY(22-36)NH₂; (SEQ ID NO. 13) or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a compound according to any one of claims 1-12,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 14. A method of decreasing excess intestinal waterand electrolyte secretion in a mammal in need thereof, said methodcomprising administering to said mammal an effective amount of acompound according to any one of claims 1-12, or a pharmaceuticallyacceptable salt thereof.
 15. A method of regulating cell proliferationin a mammal in need thereof, said method comprising administering tosaid mammal an effective amount of a compound according to any one ofclaims 1-12, or a pharmaceutically acceptable salt thereof.
 16. A methodof claim 15, wherein said cell is a gastrointestinal cell.
 17. A methodof claim 15, wherein said cell is an epithelial cell.
 18. A method ofaugmenting nutrient transport in a mammal in need thereof, said methodcomprising administering to said mammal an effective amount of acompound according to any one of claims 1-12, or a pharmaceuticallyacceptable salt thereof.
 19. A method of regulating lipolysis in amammal in need thereof, said method comprising administering to saidmammal an effective amount of a compound according to any one of claims1-12, or a pharmaceutically acceptable salt thereof.
 20. A method ofregulating blood flow in a mammal in need thereof, said methodcomprising administering to said mammal an effective amount of acompound according to any one of claims 1-12, or a pharmaceuticallyacceptable salt thereof.
 21. A method of facilitating weight loss,appetite decrease, weight maintenance, treating obesity, treatingdiabetes, treating complications of diabetes including retinopathy, ortreating cardiovascular disorders in a mammal in need thereof, saidmethod comprising administering to said mammal an effective amount of acompound according to any one of claims 1-12, or a pharmaceuticallyacceptable salt thereof.
 22. A method according to claim 21, whereinexcessive weight is a contributing factor to a disease or conditionincluding hypertension, diabetes, dyslipidemia, cardiovascular disease,gall stones, osteoarthritis and cancers.
 23. A method according to claim22, wherein said facilitation of weight loss reduces the likelihood ofsuch diseases or conditions or where said facilitation of weight losscomprises at least part of a treatment for such diseases or conditions.24. A method of antagonizing the effects of PYY(3-36) in a mammal inneed thereof, said method comprising administering to said mammal aneffective amount of a compound according to any one of claims 1-12, or apharmaceutically acceptable salt thereof, wherein said compound is a PYYantagonist.
 25. A method according to claim 24, wherein said antagonisteffects in said mammal comprise facilitating weight gain, facilitatingmaintenance in weight, and/or facilitating appetite increase.
 26. Amethod according to claim 25, wherein said facilitating weight gain,facilitating maintenance in weight, and/or facilitating appetiteincrease is indicated in a mammal having a disease or disorder, or undergoing a treatment, accompanied by weight loss.
 27. A method according toclaim 26, wherein said diseases or disorders accompanied by weight lossinclude anorexia, bulimia, cancer cachexia, AIDS, wasting, cachexia, andwasting in frail elderly.
 28. A method according to claim 26, whereinsaid treatment accompanied by weight loss comprises chemotherapy,radiation therapy, temporary or permanent immobilization, or dialysis.